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.

Costs and consequences of over-investigation of minor transfusion reactions.

BACKGROUND: Adverse transfusion events create a direct cost burden on the healthcare system through increased morbidity, mortality, extra investigations for diagnosis, patient treatment and increased use of hospital resources. Understanding the costs and impact minor transfusion reactions have on the healthcare system presents an opportunity for potential cost savings and improved clinical practice. AIMS: To determine the cost associated with investigating minor transfusion reactions, to identify opportunities to improve the management of blood transfusion reactions and potential cost savings through the application of current national guidelines. METHODS: A retrospective review of all suspected transfusion reactions reported to the laboratory over a 6-year period was performed. Reports were assessed for appropriateness of clinical management and associated investigations. Cost of inappropriate investigations and associated blood product discard was calculated using current national tariffs. RESULTS: Of the 274 reports, febrile non-haemolytic transfusion reactions were the most common reactions, with 96 (35%) cases. One hundred forty-eight patients were unnecessarily investigated for suspected transfusion reactions totalling AU$ 32 427.00. The initial total value of partially discarded blood products was AU$ 55 656.00. CONCLUSION: The study demonstrated that unnecessary investigation of minor transfusion reactions adds a significant financial burden to the healthcare system.

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).

A review of electronic medical records and safe transfusion practice for guideline development.

BACKGROUND AND OBJECTIVES: Electronic medical records (EMRs) are often composed of multiple interlinking systems, each serving a particular task, including transfusion ordering and administration. Transfusion may not be prioritized when developing or implementing electronic platforms. Uniform guidelines may assist information technology (IT) developers, institutions and healthcare workforces to progress with shared goals. MATERIALS AND METHODS: A narrative review of current clinical guidance, benefits and risks of electronic systems for clinical transfusion practice was combined with feedback from experienced transfusion practitioners. RESULTS: There is opportunity to improve the safety, quality and efficiency of transfusion practice, particularly through decision support and better identification procedures, by incorporating transfusion practice into EMRs. However, these benefits should not be assumed, as poorly designed processes within the electronic systems and the critically important electronic-human process interfaces may increase risk while creating the impression of safety. CONCLUSION: Guidelines should enable healthcare and IT industries to work constructively together so that each implementation provides assurance of safe practice.

Perceptions on consumer information in transfusion. A qualitative study of consumers and prescribers.

BACKGROUND AND OBJECTIVES: Fresh blood product transfusion requires patient education for fully informed consent, and written consumer information is frequently used. Few studies have examined consumer preferences regarding written and verbal transfusion information provided. As a qualitative study, this research was designed to explore participant understanding and by analysing and integrating themes, generate a model to understand how transfusion information should be developed and used in practice. MATERIALS AND METHODS: Semi-structured interviews were conducted with healthcare consumers of transfusion information from various hospital clinical departments. Transcripts were coded to qualitatively compare nature/extent of content and opinions regarding transfusion information through thematic analysis. RESULTS: Analysis identified themes relating to healthcare engagement, purpose of information, mode of delivery and content delivered. Differences were identified between perceived purpose of information provided to consumers between 13 transfusion prescribers and consumers. Prescribers viewed information as a tool for obtaining informed consent, whereas consumers desired reassurance and knowledge. Consumers described both the specialized nature and volume of information as limiting their ability to question professionals on whom they were dependent. Information provided should be tailored to consumers and utilize simple, succinct explanations. CONCLUSION: Both groups were satisfied with written information adjunctive to verbal information. These findings will be used to redesign transfusion information and may be employed at the bedside when discussing transfusion. They may have implications for consumer information in other settings.

Effect of anemia on muscle oxygen saturation during submaximal exercise.

BACKGROUND: Objective measures to assess the need for transfusion in chronic anemia are lacking. Near-infrared spectroscopy may be used, but there is wide variability. Assessment of muscle oxygen saturation (SmO2 ) during exercise could be used to measure the impact of anemia on performance of everyday activities. STUDY DESIGN AND METHODS: Hematology patients and controls were recruited to undertake a 6-minute walk test (6MWT) and a 20-second isometric handgrip exercise. Muscle oxygen saturation in the exercising muscles was measured before and during exercise. Changes in saturation during exercise were described. Correlations between identified variables, hemoglobin concentration, and 6MWT distance were undertaken. The effect of transfusion was assessed on a transfused subset. RESULTS: There were 95 sets of exercises conducted in 74 participants. Baseline SmO2 correlated with hemoglobin concentration and negatively with 6MWT distance. Paradoxically, a higher hemoglobin was associated with a greater SmO2 fall during the 6MWT, likely due to greater consumption from improved walk distances. The fall in SmO2 was independent of hemoglobin during isometric contraction, although levels were lower during contraction due to the lower starting SmO2 . There was a longer time to peak SmO2 during recovery following isometric exercise in anemia. There were 17 paired tests following a change in hemoglobin, with SmO2 not predicting improvement in those who had improved exercise capacity. CONCLUSION: While baseline SmO2 correlated with hemoglobin concentration, the correlation was not strong enough to predict transfusion requirements. Recovery after isometric forearm contraction correlated with hemoglobin and warrants further investigation.

Genetic and Molecular Testing in Thrombosis and Hemostasis: Informing Surveillance, Treatment, and Prognosis.

The understanding of molecular mechanisms brought about by the rapid expansion of gene sequencing has helped to characterize molecular interactions underpinning normal hemostasis and identify inherited and acquired risks for thrombosis and hemorrhage. The widespread availability of molecular testing may serve to replace some currently available investigations with more precise diagnostic tools and add to phenotypic tests. Molecular studies will increasingly enable prenatal diagnosis, confirm difficult diagnostic challenges, early intervention, and assist in prognostication. This approach facilitates specific individualization of treatment options, with personally targeted therapy expected to increase. There remain many challenges, however, in the clinic. Prior to any test there should be consideration of how the results may influence treatment, and also how they may affect the patient within their familial and social environments. Massive parallel sequencing has the capacity to produce results that create uncertainty that needs to be considered prior to testing. In this context, the potential benefits of adding phenotypic and genotypic personal data to large databases should be discussed with patients. There is a paradox in that personalized medicine is dependent on large datasets to interpret the significance of genetic variation. This review will provide an outline of specific current and emerging roles for molecular testing for the personalization of care in the practice of thrombosis and hemostasis and highlight principles that can be implemented as new opportunities inevitably arise with the rapid expansion of knowledge from genomics.

Cold reacting anti-M causing delayed hemolytic disease of the newborn.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) is due to passively transferred maternal antibodies directed against fetal red blood cell (RBC) antigens and can lead to severe morbidity and mortality. Anti-M is usually a naturally occurring antibody of low clinical significance, although occasionally severe cases of HDFN are seen. CASE REPORTS: Two M+ sisters are presented, each developing hemolysis during the first 2 weeks of life due to maternal anti-M, resulting in severe anemia and requiring blood transfusion. RBC agglutination was observed in peripheral blood samples of both infants at room temperature with dissociation at 37°C. Maternal anti-M detected by column indirect agglutination technique, was of low titer (1:16) and demonstrated low thermal amplitude, reacting in saline at 4°C but was not detectable in saline at 37°C. CONCLUSIONS: Anti-M of low thermal amplitude may cause hemolytic disease of the newborn with laboratory features resembling cold agglutinin disease.

First trimester ferritin screening for pre-delivery anaemia as a patient blood management strategy.

OBJECTIVES: To determine the optimum approach and timing to screen for iron deficiency in pregnancy. BACKGROUND: There is a lack of consensus on identifying and treating iron deficiency during pregnancy. Patient blood management programs may be refined by evaluating outcomes. METHODS: Retrospective data collection on women delivering prior to and following implementation of patient blood management interventions. Ferritin, transferrin saturation and haemoglobin levels were evaluated in first and second trimesters as predictors of pre-delivery anaemia. The optimum time to screen was determined. Comparison with results following a quality improvement intervention was undertaken. A separate retrospective study was performed to validate the predictive value of ferritin using data extracted from the laboratory information system. RESULTS: Ferritin and transferrin saturation in first trimester detected women who subsequently had anaemia pre-delivery, with ferritin being most discriminatory. Both were superior to haemoglobin concentration. Iron studies in second trimester did not predict pre-delivery anaemia and haemoglobin remained poorly discriminatory. Iron studies lost predictive value when a systematic program ensured treatment of iron depletion during pregnancy. The ability of ferritin to predict pre-delivery anaemia in the first, but not the second, trimester was confirmed on the validation cohort. CONCLUSION: First trimester serum ferritin may identify candidates for iron therapy during pregnancy. This strategy may be preferable to haemoglobin screening alone or universal replacement in centres at low risk of anaemia.

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.

Managing hypogammaglobulinaemia secondary to haematological malignancies in Australia and New Zealand: a clinician survey.

BACKGROUND: Acquired hypogammaglobulinaemia secondary to haematological malignancies is associated with increased infection risk. Immunoglobulin (Ig) replacement reduces major infections but not mortality, and is costly. No prospective randomised trials have compared Ig replacement with prophylactic antibiotics. AIMS: To identify variation in current practice regarding management of secondary hypogammaglobulinaemia in Australia and New Zealand, to identify barriers to best practice, and to inform the development of a clinical trial assessing antibiotic prophylaxis in secondary hypogammaglobulinaemia. METHODS: We conducted an online survey of current clinical practice regarding management of secondary hypogammaglobulinaemia among haematologists in Australia and New Zealand. RESULTS: Seventy-two haematologists responded; 89% of whom reported commencing Ig replacement for secondary hypogammaglobulinaemia in the setting of recurrent or severe infection. Most monitored trough immunoglobulin G levels, most often 3 monthly. Criteria for stopping Ig replacement varied. Most respondents recommended influenza and pneumococcal vaccination, while only 21% reported using antibiotic prophylaxis. Few respondents (3%) reported prescribing prophylactic antibiotics before commencing Ig replacement. Most reported an interest in recruiting patients to a clinical trial comparing Ig replacement with prophylactic antibiotics. CONCLUSION: In comparison to limited international data, this survey finds variation in practice, which may be due to differences in local policies governing access to Ig. These findings highlight the need for research into the indications for Ig commencement and cessation, and will inform design of prospective trials of infection prevention in secondary hypogammaglobulinaemia.

Misinterpretation of blood group and antibody screen leading to serious errors in RhD immunoglobulin administration: A report on first two years of data from Serious Transfusion Incident Reporting program.

The Serious Transfusion Incident Reporting program (STIR) commenced haemovigilance in relation to RhD immunoglobulin (Ig) administration in 2015. During two years of reporting, 21 reports relating to RhD Ig administration were received. Thirty-three percent (7/21) were related to omission of RhD Ig, putting women at risk of RhD alloimmunisation and adverse consequences in future pregnancies. A recent case reported to STIR highlights poor communication and misinterpretation of pathology results leading to significant morbidity from haemolysis in the fetus. STIR makes recommendations related to education of staff and communication between clinical and laboratory staff to improve the safety of patient care.

Screening test for direct oral anticoagulants with the dilute Russell viper venom time.

OBJECTIVES: To evaluate the dilute Russell viper venom time (DRVVT) for the detection of direct-acting oral anticoagulants (DOACs) and to investigate the effect of DOACS on coagulation assays. METHODS: Patients with DOACs and controls had plasma levels determined by an anti-Xa assay and dilute thrombin clotting time (TCT). Levels were correlated with the DRVVT as well as TCT, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, protein C, protein S and antithrombin levels. The utility of the DRVVT for detecting clinically significant levels of DOACs was evaluated. RESULTS: There were 44 samples from patients taking dabigatran, 83 with rivaroxaban, 18 with apixaban and 55 controls. The PT and APTT failed to detect clinically significant doses of anticoagulants adequately. The TCT was increased in patients taking dabigatran and normal in controls and patients on FXa inhibitors. There was a linear correlation with all DOAC levels and the DRVVT, with moderate precision, but it showed high sensitivity (95%) and specificity (90%) for clinically significant DOAC levels. CONCLUSION: The DRVVT detects clinically significant levels of DOACs and, in conjunction with the TCT, may be used as a screen for the presence and type of DOAC.

Unified infusion rates for 10% intravenous immunoglobulin.

Although manufacturers recommend varying infusion rates for differing intravenous immunoglobulin products (IVIg), there may be improved efficiency and reduced potential for error with the application of a single infusion policy for all IVIg products. During the transition from a 6% to a 10% IVIg, we prospectively evaluated patient reported adverse reactions to IVIg with the 10% product (Intragam 10) given at a rate faster than recommended by the manufacturer. While there was a significant increase in the rate of immediate infusion reactions when compared with the previous IVIg preparation (Intragam P), there was no increase in the rate of reactions post infusion. The rate of reactions was within previously reported expectations for other IVIg products. All reactions were minor, requiring no or minimal intervention and few impacted significantly on the quality of life. Despite an active haemovigilance program, minor adverse reactions were generally not reported. Our results suggest that a fast single rate of IVIg infusion is safe, and may minimise patient attendance and hospital resources with acceptable safety. In implementing a strategy to increase IVIg infusion rates an active process to monitor safety is preferred over standard haemovigiliance or pharmacovigilance processes.

Postpartum obstetric red cell transfusion practice: A retrospective study in a tertiary obstetric centre.

BACKGROUND: Traditional management of anaemia due to postpartum haemorrhage (PPH) has relied upon salvage therapy with red cell transfusion. Recently published guidance recommends a change in approach toward holistic patient blood management. AIMS: To determine whether postpartum red cell transfusion practices are consistent with best practice and to identify opportunities for improvement. MATERIALS AND METHODS: A retrospective audit of postpartum red cell transfusions was conducted at a tertiary level obstetrics unit. Relevant clinical and laboratory data were collected for all cases of postpartum red cell transfusions and PPH. Clinical decision making and appropriateness of transfusions were evaluated. RESULTS: Among the 3235 women who delivered in 2013, 110 (3.4%) received a postpartum red cell transfusion. About 101 of the transfusions were associated with primary PPH. Overall PPH complicated 460 (14.2%) deliveries. Antenatal anaemia was identified as a major correctable risk factor for transfusion in women who experienced PPH (odds ratio 6.55, 95% CI: 3.17-13.6). Volume of blood loss and the aetiology of PPH were additional risk factors for transfusion. Transfusion was associated with lower birth weight and increased maternal length of stay. Transfusion triggers were more likely to be appropriate when transfusion took place in the operating theatre, within 12 h of delivery and when prescribed by anaesthetists. Post-transfusion Hb levels were uniformly above target for all women transfused. CONCLUSIONS: A significant number of red cell transfusions were outside the recommendations of the new guidelines. Maximising red cell mass during pregnancy and improving transfusion practices were identified as opportunities for future improvement.