Protracted fibrinolysis resistance following cardiac surgery with cardiopulmonary bypass: A prospective observational study of clinical associations and patient outcomes.

BACKGROUND: Surgery on cardiopulmonary bypass (CPB) elicits a pleiomorphic systemic host response which, when severe, requires prolonged intensive care support. Given the substantial cross-talk between inflammation, coagulation, and fibrinolysis, the aim of this hypothesis-generating observational study was to document the kinetics of fibrinolysis recovery post-CPB using ClotPro® point-of-care viscoelastometry. Tissue plasminogen activator-induced clot lysis time (TPA LT, s) was correlated with surgical risk, disease severity, organ dysfunction and intensive care length of stay (ICU LOS). RESULTS: In 52 patients following CPB, TPA LT measured on the first post-operative day (D1) correlated with surgical risk (EuroScore II, Spearman's rho .39, p < .01), time on CPB (rho = .35, p = .04), disease severity (APACHE II, rho = .52, p < .001) and organ dysfunction (SOFA, rho = .51, p < .001) scores, duration of invasive ventilation (rho = .46, p < .01), and renal function (eGFR, rho = -.65, p < .001). In a generalized linear regression model containing TPA LT, CPB run time and markers of organ function, only TPA LT was independently associated with the ICU LOS (odds ratio 1.03 [95% CI 1.01-1.05], p = .01). In a latent variables analysis, the association between TPA LT and the ICU LOS was not mediated by renal function and thus, by inference, variation in the clearance of intraoperative tranexamic acid. CONCLUSIONS: This observational hypothesis-generating study in patients undergoing cardiac surgery with cardiopulmonary bypass demonstrated an association between the severity of fibrinolysis resistance, measured on the first post-operative day, and the need for extended postoperative ICU level support. Further examination of the role of persistent fibrinolysis resistance on the clinical outcomes in this patient cohort is warranted through large-scale, well-designed clinical studies.

Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study.

BACKGROUND: Fibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET). METHODS: In prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET. RESULTS: Distinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion. CONCLUSIONS: ClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (ii) guide corrective treatment and (iii) monitor in real-time the treatment effect. Such a precision medicine and personalised treatment approach to the management of fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients. TRIAL REGISTRATION: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov NCT05540834 ; retrospectively registered September 15th 2022).

Achieving haemostasis in thrombocytopenia in remote settings: an in vitro comparison of frozen and lyophilized products.

BACKGROUND: Platelet concentrates have a limited shelf life due to room temperature storage and therefore, are not kept in regional centres where turnover is low. Cryopreserved platelets have been proposed as an alternative to platelet transfusion in austere circumstances and fibrinogen concentrate has improved thromboelastometry parameters in thrombocytopenia. This study compared the ability of stored haemostatic products and platelets to correct thromboelastometry parameters in thrombocytopenia. MATERIALS AND METHODS: Blood from eight patients with severe thrombocytopenia was combined with platelet concentrates, cryoprecipitate, fibrinogen concentrate, factor VIII, factor XIII and cryopreserved platelets in ratios equivalent to transfusion. Tissue factor initiated thromboelastometry (EXTEM) was compared between the products. RESULTS: EXTEM amplitude at 20 minutes (A20) improved by 13.1 mm with platelets (p<0.01). The 5mm increase in A20 seen with cryoprecipitate (p=0.06) was not statistically different from platelets (p=0.19). No improvement in A20 was observed with cryopreserved platelets or factor concentrates. EXTEM clotting times (CT) improved with cryopreserved platelets (19.4 s, p=0.001) and cryoprecipitate (24.1 s, p<0.05), but not fibrinogen, and both were superior to platelets (9.9 s, p<0.05). Clotting concentrates did not improve EXTEM parameters although further studies suggested the improvement in A20 was largely driven by higher fibrinogen concentrations in cryoprecipitate. DISCUSSION: These results suggest that cryopreserved platelets enhance clot initiation but do not contribute to clot strength in thrombocytopenia. When platelets are not available for transfusion, cryoprecipitate may be of value, however this requires further clinical studies.

Superior Hemostatic and Wound-Healing Properties of Gel and Sponge Forms of Nonoxidized Cellulose Nanofibers: In Vitro and In Vivo Studies.

Many materials have been engineered and commercialized as hemostatic agents. However, there is still a gap in the availability of hemostats that offer biocompatibility and biodegradability in combination with effective hemostatic properties. Cellulose nanofibers are investigated as hemostatic materials with most studies focusing on oxidized cellulose-derived hemostats. The recent studies demonstrate that by optimizing the morphological properties of nonoxidized cellulose nanofibers (CNFs) enhanced hemostasis is achieved. Herein, the hemostatic and wound-healing properties of CNFs with optimized morphology using two forms, gel, and sponge is investigated. In vitro thromboelastometry studies demonstrate that CNFs reduce clotting time by 68% (±SE 2%) and 88% (±SE 5%) in gel and sponge forms, respectively. In an in vivo murine liver injury model, CNFs significantly reduce blood loss by 38% (±SE 10%). The pH-neutral CNFs do not damage red blood cells, nor do they impede the proliferation of fibroblast or endothelial cells. Subcutaneously-implanted CNFs show a foreign body reaction resolving with the degradation of CNFs on histological examination and there is no scarring in the skin after 8 weeks. Demonstrating superior hemostatic performance in a variety of forms, as well as biocompatibility and biodegradability, CNFs hold significant potential for use in surgical and first-aid environments.

Non-oxidized cellulose nanofibers as a topical hemostat: In vitro thromboelastometry studies of structure vs function.

Hemorrhage remains a significant cause of morbidity and mortality following trauma and during complex surgeries. A variety of nanomaterials, including oxidized cellulose nanofibers (OCNFs), have been studied to overcome the disadvantages of current commercial topical hemostats. However, the relationship between nano-structural characteristics and hemostatic efficacy of non-oxidized cellulose nanofibers (CNFs) has not been elucidated. Herein, we present the first report of the correlation between structure and hemostatic performance of CNFs. In vitro thromboelastometry studies on CNFs, synthesized by ball-milling, showed that there is an optimum balance point between the aspect ratio (AR) and specific surface area (SSA) of nanofibers in terms of their maximum contribution to platelet function and plasma coagulation. The optimized CNFs with high SSA (17 m2/g) and a high AR (166) shortened normal whole blood clotting time by 68 %, outperforming cellulose-based hemostats. Additionally, CNFs reduced clotting time in platelet-deficient blood (by 80 %) and heparinized blood (by 54 %).

Red Cell and Reticulocyte Parameters for the Detection of Iron Deficiency in Pregnancy.

BACKGROUND: Iron deficiency is a common complication of pregnancy and may lead to anemia as pregnancy progresses. Routine screening tests in pregnancy include hemoglobin levels, but in most centers not a serum ferritin. Advances in red cell and reticulocyte indices on automated blood counters have the potential to detect iron deficiency earlier, but pregnancy is associated with a rapid expansion of the red cell mass and parameters based on the entire erythrocyte population are less sensitive to changes. The objective of this study was to assess whether the Red Cell Size Factor and associated reticulocyte based indices can enable single-platform iron deficiency screening in pregnancy. METHODS: Pregnant women had ferritin measured with blood counts and reticulocytes on a Beckman DxH800. The ability of the red cell size factor (RSF) and mean reticulocyte volume (MRV) to detect iron deficiency (ferritin < 10 µg/L) or early iron deficiency (ferritin < 30 µg/L) was assessed by comparing receiver operator characteristic curves and areas under the curve (AUC). RESULTS: RSF (AUC 0.80) and MRV (AUC 0.80) were both acceptable for detecting iron deficiency, but were not statistically superior to mean cell volume (MCV; AUC 0.77, p = 0.1). However, the optimal cut point for MCV was 86 fL, well above the accepted lower limit of normal. All parameters were poor at detecting early iron deficiency. CONCLUSIONS: Iron deficiency can be detected in pregnancy with red cell and reticulocyte parameters. While a low MCV is suboptimal as a screening test for iron deficiency, an MCV of 86 fL provides similar performance to the other red cell parameters studied.

Comparison of the bone marrow trephine sample quality between OnControl drill system and the Jamshidi needle.

INTRODUCTION: Bone marrow biopsies are a key diagnostic and monitoring intervention in haematology with manual bone marrow techniques the established method of choice. Powered biopsy devices are now available, but are not widely used in haematology. This study compared the quality of bone marrow trephines obtained with the Jamshidi needle and OnControl powered drill system. METHODS: Retrospective analysis was undertaken on trephine samples prior to and after implementation of the OnControl drill system. Trephine size and quality were assessed independently by three pathologists and compared between techniques and operators using nonparametric tests. RESULTS: There were 164 samples assessed (Jamshidi n = 69, OnControl, same site as aspirate n = 48, OnControl, separate site from aspirate n = 47). The assessable and total length were similar between the Jamshidi and OnControl techniques, with increased crush artefact observed with the OnControl drill (P < 0.001). Using a separate puncture site for trephine collection and aspirate did not reduce the artefact seen with the OnControl system (P = 0.274). Smaller samples (P < 0.001) and an increase in crushed (P = 0.009) and connective tissue (P = 0.002) were seen in trephines obtained by nonlaboratory-based trainees, regardless of the needle used or their stage of training, compared to laboratory trainees. CONCLUSIONS: Trephines obtained by either method had similar assessable areas. The OnControl system was associated with more artefact, a finding in line with previous studies. There was no improvement by sampling the trephine from a separate site to the aspirate. Laboratory-based trainees who reviewed marrow morphology produced trephines with better assessable length than those not based in the laboratory.

Transfusion demand control strategies: potential efficacy of hospital and regional interventions.

INTRODUCTION: Contingency plans have been developed to direct appropriate responses to blood shortages. Planning requires an understanding of the potential savings of different conservation strategies. METHOD: The Australian Capital Territory (ACT) Haemovigilance and ACT Pathology transfusion databases were reviewed from March to September 2003. All transfusion episodes were prioritised in accordance with the Australian National Blood Supply Contingency Plan. The number of red cell transfusions related to various indications, their appropriateness and acuity was determined. The potential reduction in red cell usage was modelled for potential red cell reduction interventions. RESULTS: There were 2305 units of red cells captured during the timeframes of the audits. This accounted for an estimated 70% of all red cell transfusions in the ACT. After correcting for the number of red cells transfused at each hospital, red cells were prioritised as category 1 in 59%, 2 in 27% and 3 in 13%. The remainder had insufficient data for classification. Transfusion for elective surgery accounted for 14.7% of red cells used, with 9.0% rated category 3 under the contingency plan. There were 17.3% of red cells transfused for inappropriate indications, when reviewed against national guidelines. After excluding inappropriate transfusions, cancelling elective surgery could potentially save a further 5.5% and 4.3% of blood utilisation for category 3 and 2 patients, respectively. Significant differences were found between hospitals. CONCLUSION: Targeting inappropriate transfusions by vetting particularly for inappropriate transfusions not only re-directs blood away from those unlikely to benefit, but is also more effective at preserving the red blood cells than other measures during times of supply limitation. Contingency planning needs to accommodate the variable case-mix in hospitals, allocate resources for transfusion medicine specialists to review every transfusion request and may be better coordinated at a jurisdictional level.

Blood transfusion prescribing in the ACT: an insight into clinical decision making.

Medical practitioners with varying levels of experience may make medical decisions in hospitals. Little is known about who is responsible for these decisions. We determined transfusion appropriateness during an audit of blood transfusion, before developing practice improvement strategies, by concurrent medical record review. The prescriber could be determined in 78% of transfusion episodes: most were specialist staff. Registrars and after-hours staff prescribed significantly fewer inappropriate transfusions. The findings have significant implications in understanding clinical decision making in the hospital setting and for the targeting of quality improvement strategies in particular.