Perioperative considerations in the paediatric patient with congenital and acquired coagulopathy.

Neonates, infants, and children undergoing major surgery or with trauma can develop severe coagulopathy perioperatively. Neonates and infants are at highest risk because their haemostatic system is not fully developed and underlying inherited bleeding disorders may not have been diagnosed before surgery. Historically, laboratory coagulation measurements have been used to diagnose and monitor coagulopathies. Contemporary dynamic monitoring strategies are evolving. Viscoelastic testing is increasingly being used to monitor coagulopathy, particularly in procedures with a high risk of bleeding. However, there is a lack of valid age-specific reference values for diagnosis and trigger or target values for appropriate therapeutic management. A promising screening tool of primary haemostasis that may be used to diagnose quantitative and qualitative platelet abnormalities is the in vitro closure time by platelet function analyser. Targeted individualised treatment strategies for haemostatic bleeding arising from inherited or acquired bleeding disorders may include measures such as tranexamic acid, administration of plasma, derived or recombinant factors such as fibrinogen concentrate, or allogeneic blood component transfusions (plasma, platelets, or cryoprecipitate). Herein we review current recommended perioperative guidelines, monitoring strategies, and treatment modalities for the paediatric patient with a coagulopathy. In the absence of data from adequately powered prospective studies, it is recommended that expert consensus be considered until additional research and validation of goal-directed perioperative bleeding management in paediatric patients is available.

Bleeding management in type 3 von Willebrand disease with anti-von Willebrand factor inhibitor: A literature review and case report.

Treatment of type 3 von Willebrand disease by infusion of von Willebrand factor (VWF) and factor VIII (FVIII) concentrates may lead to the development of anti-VWF antibodies, challenging haemostasis management. The systematic review of the literature presented here retrieved 15 such cases (surgery n = 11, bleeding n = 4). The heterogeneous patient management mostly involved continuous infusion of FVIII, or recombinant FVIIa together with various other strategies. Off-label infusion of the bispecific monoclonal antibody emicizumab was prescribed in three cases and in a complex local case, ultimately well-controlled with emicizumab. This illustrates the fact that emicizumab appears as a therapeutic option in this context of allo-immunisation.

Comparison of two techniques of administering the Valsalva manoeuvre in patients under general anaesthesia: A randomised controlled study.

Background and Aims: Surgeons often request a Valsalva manoeuvre (VM) at the end of surgery (head-neck surgery, craniotomy) to check haemostasis and to unmask covert venous bleeders. We aimed to compare an anaesthesia machine-generated objective technique for delivering VM under pressure-control (PC) mode with the traditional subjective technique of delivering VM in manual mode. Methods: This randomised controlled study included 60 adult patients randomised to manual (Group M) and controlled ventilation (Group C) groups. Our primary outcome measure was internal jugular vein (IJV) diameter at pre-determined time points (T0 = baseline, T1 = VM initiation, T2 = 20 s after VM initiation, T3 = immediately after VM release, and T4 = 1 min, T5 = 2 min and T6 = 5 min post-VM release). Secondary outcome measures included mean arterial pressure (MAP), heart rate, time to desired plateau airway pressure, number of patients with bleeders unmasked and surgeon satisfaction. Independent/paired sample t-tests were applied. Results are expressed as mean (standard deviation), mean difference (95% confidence interval), dotted box-whisker plots and trendlines. P <0.05 is considered statistically significant. Results: Mean differences in diameter changes in IJV (in centimetres) in the mediolateral and anteroposterior directions between Group C and Group M were -0.136 (-0.227, -0.044) and -0.073 (-0.143, -0.002), respectively. VM in the PC mode produced more significant IJV dilatation (P = 0.004, P = 0.044). MAP at T0 and T1 was comparable. At T2 and T3, there was a more significant fall in MAP in Group C versus Group M (P = 0.018 and P = 0.021, respectively). At T4, T5 and T6, MAP was comparable. Conclusion: Performing VM in PC mode is a better technique based on IJV diameter, haemodynamics, bleeder unmasking and surgeon satisfaction.

Silk fibroin-gelatine haemostatic sponge loaded with thrombin for wound haemostasis and tissue regeneration.

Background: Wound haemostasis is an important part of clinical treatments, especially treatments for patients with avulsion injury, destructive injury and large-scale soft tissue injury. Therefore, developing fast and effective haemostatic materials is critical. This study aimed to design a novel and efficient silk fibroin-gelatine composite haemostatic sponge loaded with thrombin (SFG@TB) to assist in wound haemostasis. Methods: The SFG@TB composite haemostatic sponge was formed with gelatine, silk fibroin and thrombin through a freeze-drying technique. First, the material characteristics of SFG@TB were measured, including the elastic modulus, swelling rate and porosity. Second, in vitro cell coculture experiments, in vivo embedding experiments and haemolytic analyses were performed to evaluate the biocompatibility of SFG@TB. Then, coagulation experiments and femoral artery and liver bleeding models were used to evaluate the haemostatic performance of SFG@TB. Finally, the ability of SFG@TB to promote tissue healing was evaluated through experiments with Sprague-Dawley rat models of injury. Results: Compared with gelatine sponges, SFG@TB exhibited outstanding mechanical properties and water absorption properties. In addition, the excellent biosafety of the composite haemostatic sponge was confirmed by cell experiments, subcutaneous embedding experiments and haemolytic analysis. Based on the in vitro coagulation test results, SFG@TB exhibited greater adhesion of red blood cells and platelets and a shorter dynamic coagulation time. Compared to the use of silk fibroin-gelatine composite haemostatic sponges or gelatine sponges, the introduction of thrombin resulted in a shorter haemostasis time and a smaller bleeding volume, as revealed by in vivo coagulation tests. The experiments with Sprague-Dawley rat models of injury indicated that SFG@TB accelerated the wound healing process and reduced scar width, which was accompanied by thicker granulation tissue. Conclusions: Overall, the SFG@TB composite haemostatic sponge, which exhibits outstanding mechanical properties, good haemostatic performance and high biosafety, promoted wound haemostasis and tissue repair. Therefore, the SFG@TB composite haemostatic sponge could be a promising material for wound haemostasis.

AKR7A5 knockout promote acute liver injury by inducing inflammatory response, oxidative stress and apoptosis in mice.

Alcohol liver disease has become a worldwide critical health problem. The ingested alcohol could be converted into acetaldehyde or combined with free fatty acids to induce the endoplasmic reticulum oxidative stress in the liver. Coincidentally, AKR7A5 has both aldehyde detoxification and antioxidant effects. Therefore, we discuss the possible role and mechanism of AKR7A5 in the acute alcohol injury of mice liver. There were four experiment groups, the C57BL/6 mice of wild-type mice (WT) or AKR7A5-/- mice (KO) were intragastrically administrated with saline or 50% ethanol at 14 mL/kg, respectively. Compared to the WT + alcohol group, abnormal liver function, disordered hepatic cord, severe congestion in the hepatic sinus and the space of the hepatic cord, occurrence of oxidative stress, DNA damage and different expressions of apoptosis-related proteins were detected in the KO + alcohol group. Meanwhile, the biological process enrichment analysis showed that the down-regulated proteins were related to the metabolism of fatty acid, the up-regulated proteins positive regulation of reactive oxygen species metabolic process, negative regulation of coagulation and haemostasis. In conclusion, single ethanol binge combined with the absence of AKR7A5 caused more severe inflammatory response, oxidative stress, apoptosis of endogenous pathways, abnormal lipids metabolism and disordered coagulation in mice liver.

Safety of Fibrinogen Concentrate for Correcting Perioperative Bleeding-Associated Hypofibrinogenemia in Adults: A Single-Center Experience.

Background: Surgery often leads to bleeding associated with hypofibrinogenemia. Supplementation with fibrinogen concentrate appears to be effective and safe, although findings from studies are inconsistent. The primary aim of this study was to assess the safety of fibrinogen concentrate during the perioperative period. Methods: This single-centre, prospective, observational study included adult patients undergoing scheduled or emergency surgery related to bleeding coagulopathy and the administration of fibrinogen concentrate. Patients were followed until their discharge from the institution. Comprehensive data were collected, including age, sex, type of surgery, associated comorbidities, anticoagulant and/or anti-aggregating therapy, and the number of blood transfusions. Laboratory data on plasma fibrinogen concentration, haemoglobin, and platelet count before and after surgery were also collected. The primary outcomes were the mortality rate at discharge and any reported thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, and myocardial infarction. Results: The study included 91 adult patients who had undergone surgery, with 29 surgeries (32%) conducted in an emergency setting. The mean age was 59.2 years, and 53.8% were male. Major bleeding occurred in 29 cases, mainly in older males and those on anticoagulant therapy. The pre-operative fibrinogen level averaged 161 mg/dL, and the average dosage of fibrinogen concentrate administered was 2.7 g. Eight patients died (8.8%), mostly due to septic or cardiogenic shock, with deaths being more frequent in emergency settings. Thromboembolic events occurred in eight patients, none of whom died. No additional adverse events directly related to the administration of fibrinogen concentrate were reported. Conclusions: Our findings suggest a favourable safety profile for fibrinogen concentrate in surgical patients, as evidenced by a low incidence of deaths and thromboembolic events, which were primarily attributed to other factors. Future research should strive to increase statistical robustness to further illuminate clinically significant patient safety measures.

Preoperative coagulation tests: A narrative review of current guidelines.

INTRODUCTION: Hemostasis tests are traditionally requested for all patients requiring any surgical act or invasive diagnostic-therapeutic procedure to prevent hemorrhagic complications. The aim of this study is to assess the necessity of requesting standard pre-procedure hemostasis tests. METHODOLOGY: A narrative literature review was conducted using the PubMed data-base. Search terms included «Hemostasis¼ or «Blood coagulation¼ in combination with «Preoperative care¼, «Preoperative period¼, or «Preoperative procedure¼. Additionally, a targeted search was performed to find recommendations from international societies related to the topic. RESULTS: A total of 233 articles were found, 17 were pre-selected, and after full-text evaluation, 14 relevant articles were identified. The targeted search yielded an additional 12 articles. The request for tests should be individualized according to the clinical history. Standardized screening questionnaires for hemostasis disorders are useful and complement the aforementioned approach. Factors such as age, ASA classification, bleeding potential-complexity of the procedure, and anesthetic technique may influence their request. DISCUSSION: The incidence of hemostasis disorders in the general population is very low, and these can mostly be detected through clinical history. Thus, it is the clinical history that should guide the need for laboratory test requests. CONCLUSIONS: Preoperative hemostasis tests should not be indiscriminately requested for all patients needing an intervention or invasive diagnostic-therapeutic procedure, but rather when there are doubts about their hemostatic competence or as advised by the nature of the procedure they are undergoing.

The hemostatic molecular mechanism of Sanguisorbae Radix's pharmacological active components based on HSA: Spectroscopic investigations, molecular docking and dynamics simulation.

The interactions between human serum albumin (HSA) and the hemostatic components of the Chinese medicine Sanguisorbae Radix (SR), specifically phenolic acid compounds such as caffeic acid (CA), ferulic acid (FA) and their 1:1 mixture (1:1) were studied to investigate the molecular mechanism underlying the hemostatic effect of SR. Network pharmacology combined with the experimental and computational data revealed that HSA is one of the hemostatic targets to SR phenolic acids. SDS-PAGE and multi-spectroscopy demonstrated that the phenolic acids bind to the Sudlow site I on HSA, altering its structure and influencing its migration velocity. There is an observed synergistic effect upon the mixture of CA and FA. Quantum chemistry, molecular docking, and molecular dynamics simulations indicate that the binding of phenolic acids to HSA is stable, and variations in binding efficiency are associated with the hydrophobicity of the substituent at the C3 position of the side chain, and also, the key amino acids and functional groups for hemostasis of SR were identified, along with the active sites that contribute to the synergistic enhancement by phenolic acids.

Real-world effectiveness of eptacog beta in patients with haemophilia and inhibitors: A multi-institutional case series.

INTRODUCTION: The management of bleeding events (BEs) in haemophilia A (HA) and B (HB) patients with inhibitors necessitates the use of bypassing agents. The recombinant factor VIIa bypassing agent eptacog beta has demonstrated efficacy at treating BEs and managing perioperative bleeding in adults in phase three clinical studies. AIM: To provide real-world descriptions of eptacog beta use for BE treatment in patients on emicizumab or eptacog beta prophylaxis. METHODS: This is a retrospective case series of 14 patients who received eptacog beta at seven haemophilia treatment centres, with HA (n = 11) or HB (n = 3) and inhibitors or anaphylaxis to factor replacement. RESULTS: Twenty-four spontaneous and traumatic BEs are described (muscle hematomas, joint hemarthroses, port site, and epistaxis) involving 11 subjects. Eptacog beta was effective for acute bleed treatment as both first-line therapy and for treatment of BEs refractory to eptacog alfa in 23/24 events. When eptacog beta was used for prophylaxis, 2/3 patients reported a decreased frequency of breakthrough BEs compared with prophylactic eptacog alfa and one patient experienced a similar frequency of breakthrough BEs compared with prophylactic activated prothrombin complex concentrate. Eptacog beta provided effective bleed control for three subjects who underwent minor surgical procedures. Treatment with eptacog beta was estimated to be 46%-72% more cost-effective than eptacog alfa. No safety concerns or adverse events were reported. CONCLUSIONS: In this case series, eptacog beta was safe, effective, and economical as first-line therapy, treatment of refractory BEs, management of perioperative bleeding, or prophylaxis in haemophilia patients with inhibitors.

Suture-based techniques versus manual compression for femoral venous haemostasis after electrophysiology procedures.

BACKGROUND AND AIMS: Methods for femoral venous haemostasis following electrophysiology (EP) procedures include manual compression (MC) and suture-based techniques such as a figure-of-eight suture secured with a hand-tied knot (Fo8HT) or a modified figure-of-eight suture secured with a 3-way stopcock (Fo8MOD). We hypothesised that short-term bleeding outcomes using the Fo8MOD approach would be superior to MC. We additionally compared outcomes between Fo8MOD and Fo8HT approaches. METHODS: We studied consecutive patients undergoing EP procedures at our institution between March and December 2023. Patients were categorised into three haemostasis groups: MC, Fo8HT and Fo8MOD. Access site complications were classified as major (requiring intervention or blood transfusion, delaying discharge or resulting in death) or minor (bleeding/haematoma requiring additional compression). RESULTS: 1089 patients were included: MC 718 (65.9%); Fo8HT 105 (9.6%); Fo8MOD 266 (24.4%). Procedures were most commonly for atrial fibrillation (52.4%), atrial flutter (10.9%), and atrioventricular nodal re-entrant tachycardia (10.1%). In patients receiving periprocedural anticoagulation (865, 79.4%), Fo8MOD associated with fewer complications than MC or Fo8HT (major: MC 2.2%, Fo8HT 6.0%, Fo8MOD 0.8%, p = .01; minor: MC 16.5%, Fo8HT 12.0%, Fo8MOD 7.4%, p = .002). In patients not receiving periprocedural anticoagulation, complications did not differ between haemostasis methods (total major and minor complications 5.8%, p = .729 for between groups rates). On multivariable logistic regression, Fo8MOD was associated with a significantly lower risk of access site complications (OR 0.29 [95% CI 0.17-0.48], p < .001), whilst intraprocedural heparinisation (OR 5.25 [2.88-9.69], p < .001) and larger maximal sheath size (OR 1.06 [1.00-1.11], p = .04) were associated with a higher risk of complications. CONCLUSION: Femoral haemostasis with Fo8MOD associates with fewer access site complications than MC and Fo8HT following EP procedures that need periprocedural anticoagulation.

Evaluation of the International Society on Thrombosis and Haemostasis definition of major bleeding in Arizona rattlesnake bites.

INTRODUCTION: In 2023, a group of experts proposed that a definition of major bleeding in pharmaceutically anticoagulated patients be used in all snakebite trials. This includes bleeding that results in death, is life-threatening, causes chronic sequelae, or consumes major healthcare resources, including bleeding into a major area or hemoglobin concentration decrease ≥20 g/L. We hypothesized that a decline in hemoglobin concentration ≥20 g/L is common but rarely clinically significant in our population of Arizona rattlesnake bite patients. METHODS: Poison center records of rattlesnake bites in humans from 2018 through 2022 were retrospectively reviewed and assessed for major bleeding by the above criteria. RESULTS: Four hundred and eighty-one patients met the inclusion criteria, of whom 265 (55.1%) had a hemoglobin concentration decrease ≥20 g/L. No patients died, and there was no evidence of bleeding into a critical organ. Three patients (1.1%) received blood transfusions. A decrease in hemoglobin concentration ≥20 g/L was 100% sensitive for identifying the major bleeding-associated outcomes; however, specificity was only 45.2%. Measures of healthcare utilization and chronic sequelae were somewhat higher in patients with a decrease in hemoglobin concentration ≥20 g/L. DISCUSSION: Laboratory manifestations of hemotoxicity were common in this population, but hemorrhage was rare. While over half of patients met the major bleeding criterion of a decline in hemoglobin concentration ≥20 g/L, only 1.1% had bleeding that was potentially life-threatening as measured by receipt of a red blood cell transfusion. None died or had bleeding into a critical area. While nonspecific for major bleeding, a drop in hemoglobin concentration correlated with worse envenomation severity: these patients received more vials of antivenom, had a higher medical bill, a longer hospital stay, and were less likely to report full recovery at 90 days. CONCLUSIONS: A decrease in hemoglobin concentration ≥20 g/L should not be used as evidence of major bleeding for Arizona rattlesnake envenomation studies, but it may have a role as an indirect marker of envenomation severity.

Evaluation of variants in the ENTPD1 and ENTPD2 genes in athletic horses with exercise-induced pulmonary haemorrhage.

BACKGROUND: Exercise-induced pulmonary haemorrhage (EIPH) in athletic horses is characterized by the presence of blood from the lungs in the tracheobronchial tree after intense exercise. Despite the high prevalence of EIPH in horses, the primary aetiology remains unknown. Variants in the genes encoding CD39 and CD39L1 (ENTPD1 and ENTPD2, respectively) were previously reported as potential genetic causes involved in EIPH pathogenesis. However, the role of these variants in haemostatic functions is unknown. RESULTS: To investigate the association between EIPH and missense variants in the ENTPD1 (rs1152296272, rs68621348, and rs68621347) and ENTPD2 genes (rs782872967), 76 Thoroughbred horses diagnosed with EIPH and 56 without clinical signs of EIPH (control group) by trachea-bronchial endoscopy were genotyped. The rs1152296272 and rs68621347 variants were linked, which explained why the same results were found in all horses. Approximately 96% and 95% of the EIPH and control horses, respectively, carried at least one nonreference allele for these variants. In contrast, 100% of the control horses and 96% of the EIPH horses were homozygous for the reference allele for the rs68621348 variant. In the EIPH group, 1.5% of the horses were homozygotes and 24% were heterozygous for the nonreference allele of the rs782872967 variant. In the control group, the nonreference allele of this variant was observed only in heterozygotes (16%). There were no significant differences between groups for any of the variants. CONCLUSIONS: The variants previously described in the genes encoding the CD39 and CD39L1 enzymes were highly present in the studied population. However, no association was found between the occurrence of EIPH and the presence of these variants in Thoroughbred horses in this study.

Haemostatic spray in the management of acute nonvariceal upper gastrointestinal bleeding in children: A single-centre experience in Singapore.

Introduction/Objectives: Haemostatic spray (HS; Hemospray) is a powder agent for endoscopic haemostasis in patients with acute upper gastrointestinal bleeding (UGIB). It has been shown to be effective and easy to administer. However, published data on efficacy and safety in children remain scarce. Our aim was to describe our experience with the use of HS in the management of UGIB. Patients and Methods: A retrospective review was conducted of patients aged 0-18 receiving HS for endoscopic haemostasis from January 2017 to December 2021. Information was obtained on demographics, clinical presentation and comorbidities. Outcomes were successful initial haemostasis and rates of re-bleeding. Results: A total of 25 applications of HS occurred in 23 patients. The median patient age was 8 years (range: 4 months to 16 years). HS was used in 17/25 (68%) applications as monotherapy. Other treatments employed were clip application and adrenaline injection. One hundred per cent initial haemostasis was achieved with three (13.0%) patients who experienced re-bleeding. All patients tolerated HS applications with no adverse events. Conclusions: Our finding supports the use of HS in the management of UGIB in children. HS, either as monotherapy or in combination with other conventional therapy, could potentially be the treatment of choice in children with UGIB with its excellent feasibility and good safety profile.

A comparative study on the haemostatic changes in kidney failure patients: Pre- and post- haemodialysis and haemodiafiltration.

BACKGROUND: Individuals with kidney failure have a compromised haemostatic system making them susceptible to both thrombosis and bleeding. OBJECTIVES: Assessment of primary haemostasis in patients treated with either haemodialysis (HD) or haemodiafiltration (HDF) was performed through the measurement of several coagulation-based tests, both pre- and post-dialysis. PATIENTS/METHODS: 41 renal failure patients and 40 controls were recruited. Platelet aggregometry, Factor XIII (FXIII), Fibrinogen, Von Willebrand Factor (VWF) and Soluble P-Selectin (sP-Sel) levels were measured. RESULTS: Maximum platelet aggregation was diminished in renal patients irrespective of aspirin intake. Post-dialysis, platelet function was exacerbated. Pre-dialysis FXIII levels were similar to the healthy cohort and became elevated post-dialysis. This elevation could not be explained by the relative decrease of water by dialysis. Fibrinogen levels were already elevated pre-dialysis and further increased post-dialysis. This elevation was associated with the relative decrease of water by dialysis. VWF levels in males were similar to the healthy cohort and became elevated post-dialysis. This elevation was associated with dialysis-related water loss. VWF antigen and activity in female patients were already elevated pre-dialysis and further increased post-dialysis with the exception of VWF activity in HDF treated female patients. sP-Sel levels were lower than those of the healthy cohort and became similar to the healthy cohort post-dialysis. This elevation could not be explained by the relative decrease of water by dialysis. CONCLUSIONS: Whilst platelet aggregometry was diminished, we noted elevated clotting factors such as fibrinogen, FXIII and VWF with no significant differences between HD and HDF-treated patients.

Comparison of two haemostasis techniques on procedural duration, postoperative pain and gastrointestinal function in pet rabbits undergoing ovariohysterectomy.

Ovariohysterectomy is a common surgical procedure in pet rabbits and one of its potential complications is postoperative gastrointestinal stasis, possibly exacerbated by prolonged surgery time. The objective of this prospective clinical study was to compare two techniques for surgical haemostasis with respect to procedural duration, postoperative pain, and return of gastrointestinal function, in 22 female rabbits undergoing ovariohysterectomy. Rabbits were assigned to one of two groups: conventional vessel ligation (CVL) and haemostasis with a vessel sealing device (VSD). The outcome variables for comparison between the two groups, recorded at 60-, 120-, 180-, and 360-minutes post anaesthesia, were duration of anaesthesia and surgery, postoperative Rabbit Grimace Scale scores, and measured food intake and faecal output. The vessel sealing device caused no appreciable blood loss. The duration of both surgery and anaesthesia was shorter in group VSD (20 ± 4 and 31 ± 6 minutes, respectively) than in group CVL (43 ± 9 and 54 ± 9 minutes, respectively) (p < 0.001). There were no differences between groups in time elapsed from the end of anaesthesia to both first food intake and first defecation. In both groups, the score of the Rabbit Grimace Scale decreased over time with statistically significant differences between 60 minutes and all the subsequent time points (p < 0.001). Vessel sealing devices may be recommended over conventional haemostasis for rabbit ovariohysterectomy to decrease the duration of surgery and anaesthesia, with potential beneficial effects on sustainability and practice workflow.

Revisiting the full blood count: Circulating blood cells and their role in coagulation.

There has been an expansion in our understanding of the multifaceted roles of circulating blood cells in regulating haemostasis and contributing to thrombosis. Notably, there is greater recognition of the interplay between coagulation with inflammation and innate immune activation and the contribution of leucocytes. The full blood count (FBC) is a time-honoured test in medicine; however, its components are often viewed in isolation and without consideration of their haemostatic and thrombotic potential. Here, we review how the individual components of the FBC, that is, haemoglobin, platelets and leucocytes, engage with the haemostatic system and focus on both their quantitative and qualitative attributes. We also explore how this information can be harnessed into better management of people with multiple long-term conditions because of their higher risk of adverse clinical events.

A call for subspecialty training programmes in women's thrombosis and haemostasis.

Multidisciplinary collaboration to create formal education/training programmes in women's thrombosis and haemostasis will ideally lead to improved knowledge and health equity and potentially improve patient outcomes.