A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple ...types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.
•The ThromboGenomics HTS test validates recent gene discoveries and detects CNVs and intronic variants.•ThromboGenomics reveals a molecular diagnosis for 37.3% of 2396 patients with BTPDs.
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There are unique complications arising from mechanical support devices but some of the long-term systemic haematological complications are indistinguishable from management problems affecting the ...care of other patients receiving intermediate to long term care in the cardiac ICU. The field of mechanical cardiac assist device (MCAD) is evolving. Despite major changes in design of these devices the most feared haematological complications have remained unchanged, namely haemolysis, pump thrombosis or thromboembolism. This review article gives an overview over the pathophysiology of MCAD related haematological complications, their management and where possible an outlook on future strategies to prevent such complications. The impact of MCAD on blood is discussed, starting with rheology, common pump mechanisms, current and future pump surface coating materials, anatomical considerations of the connection of the circuit and design of the circuit itself. Moreover, the duration of the cardiovascular support, impact of bleeding complications and other patient factors. This article also covers the impact of long term mechanical cardiac support on the properties of platelets, the anticoagulation strategies and a basic guide to the differential diagnosis of haemolysis is reviewed. The section on anaemia considers anaemia in the wider perioperative setting for patients in critical care having undergone cardiac surgery and also discusses transfusion alternatives.
Administration of coagulation factor concentrates to treat bleeding after cardiac surgery with cardiopulmonary bypass might be a strategy for reducing allogeneic blood transfusions, particularly for ...patients treated with warfarin preoperatively. We performed an exploratory analysis on whether the use of prothrombin complex concentrate (PCC) is safe and effective compared with fresh frozen plasma (FFP) to treat coagulopathy after pulmonary endarterectomy surgery with deep hypothermic circulatory arrest.
Consecutive adult patients who underwent pulmonary endarterectomy surgery between January 2010 and September 2012 and received PCC or FFP to treat coagulopathy were studied. Blood loss during the first 12 hours of admission to the intensive care unit and patient outcomes were compared with propensity score adjustment.
Three hundred fifty-one patients underwent pulmonary endarterectomy surgery, all of whom had warfarin discontinued for up to 5 days before surgery; bleeding complications requiring transfusion of blood products were observed in 108 (31%) patients. Of those, 55 received only FFP and 45 received only PCC, whereas 8 received both. Blood loss was significantly greater in the FFP group compared with the PCC group after 12 hours (median interquartile range, 650 mL 325-1075 vs 277 mL 175-608, P = 0.008). However, there was no difference in the frequency of patients receiving a red blood cell transfusion (number percent, 44 80% vs 34 76%, P = 0.594) or in the number of units of red blood cells transfused (median interquartile range, 2 1-4 vs 3 1-5 units, P = 0.181). The final propensity score included preoperative international normalized ratio, postoperative activated partial thromboplastin time, and postoperative platelet count. After inclusion of the propensity score in the regression analyses, there were no differences between patients receiving only PCC and patients receiving only FFP in the need for renal replacement therapy (odds ratio OR 2.39, 95% confidence interval CI 0.51-11.20, P = 0.27), 30-day-mortality (OR 0.32, 95% CI 0.03-3.36, P = 0.35), intracranial hemorrhage (OR 0.73, 95% CI 0.14-3.89, P = 0.71), hospital length of stay (hazard ratio 0.77, 95% CI 0.50-1.19, P = 0.24), or duration of intensive care stay (hazard ratio 0.91, 95% CI 0.59-1.40, P = 0.66).
This retrospective analysis suggests that PCC may be an alternative to FFP in patients previously treated with warfarin who are coagulopathic after major cardiac surgery. Randomized controlled studies powered to evaluate efficacy and important postoperative outcomes for patients receiving PCC versus FFP for coagulopathic bleeding after cardiopulmonary bypass are warranted.
Acquired hypofibrinogenemia is most frequently caused by hemodilution and consumption of clotting factors. The aggressive replacement of fibrinogen has become one of the core principles of modern ...management of massive hemorrhage. The best method for determining the patient's fibrinogen level remains controversial, and particularly in acquired dysfibrinogenemia, could have major therapeutic implications depending on which quantification method is chosen. This review introduces the available laboratory and point-of-care methods and discusses the relative advantages and limitations. It also discusses current strategies for the correction of hypofibrinogenemia.
Sickle cell disease (SCD) is an inherited, progressively debilitating blood disorder. Emerging gene therapies (GTx) may lead to a complete remission, the benefits of such can only be realized if GTx ...is affordable and accessible in the low-and middle-income countries (LMIC) with the greatest SCD burden. To estimate the health impacts and country-specific value-based prices (VBP) of a future gene therapy for SCD using a cost-utility model framework. We developed a lifetime Markov model to compare the costs and health outcomes of GTx versus standard of care for SCD. We modeled populations in seven LMICs and six high-income countries (HICs) estimating lifetime costs and disability-adjusted life-years (DALYs) in comparison to estimates of a country's cost-effectiveness threshold. Each country's unique VBP for GTx was calculated via threshold analysis. Relative to SOC treatment alone, we found that hypothetical GTx reduced the number of people symptomatic with SCD over time leading to fewer DALYs. Across countries, VBPs ranged from $3.6 million (US) to $700 (Uganda). Our results indicate a wide range of GTx prices are required if it is to be made widely available and may inform burden and affordability for 'target product profiles' of GTx in SCD.
Heparin-Induced Thrombocytopenia and Vascular Surgery Besser, Martin W.; Vuylsteke, Alain
Journal of cardiothoracic and vascular anesthesia,
October 2017, 2017-10-00, 20171001, Letnik:
31, Številka:
5
Journal Article
COVID-19 has resulted in an exponential increase in patients with severe respiratory failure requiring extracorporeal membrane oxygenation (ECMO). Patients on ECMO regularly require high volumes of ...blood and blood products but, so far, there has been no comparison of transfusion requirements between COVID-19 and non-COVID-19. Using electronic patient records at two major UK ECMO centres, Royal Papworth Hospital and University Hospital South Manchester, we reviewed the transfusion requirements of patients requiring ECMO between January 2019 to December 2021. A total of 271 patients, including 168 COVID-19 patients were available for analysis. Since COVID-19 patients spent almost twice as long on ECMO (27.1 vs. 14.16 days,
≤ 0.0001) we indexed transfusion in both groups to days on ECMO to allow comparison. COVID-19 patients required less red blood cells (RBC) per day (0.408 vs. 0.996,
= 0.0005) but more cryoprecipitate transfusions (0.117 vs. 0.106,
= 0.022) compared to non-COVID-19 patients. COVID-19 patients had more than double the mortality of non-COVID-19 patients (47% vs. 20.4%,
= 0.0001) and those who died during the study period had higher platelet transfusion requirements (
= 0.007) than their non-COVID-19 counterparts. Transfusion requirements and coagulopathy differ between COVID-19 and non-COVID-19 patients. The distinctly different transfusion patterns between the two groups remain difficult to interpret, but further investigations may help explain the haematological aspects of severe COVID-19 infection.
Aim:
We explored the relationship between activated clotting time (ACT) and activated partial thromboplastin time (aPTT) when used to monitor anticoagulation in patients undergoing extracorporeal ...membrane oxygenation (ECMO) support.
Methods:
Data obtained in patients undergoing ECMO support between October 2012 and August 2013 in a single centre were reviewed. Clinical data were extracted from our Clinical Information System and ECMO database. ACT and aPTT values were paired when taken from the same patient, with the ACT preceding the aPTT and the heparin infusion rate was kept constant between samples. The aPTT and ACT were normalized by dividing by the mean of their respective reference ranges and are referred to as APR and N-ACT, respectively. Bivariate analysis and Bland-Altman plots were used to assess correlation and agreement. Mixed effects regression was used to model the effects of variables, including platelet count, creatinine and urea levels, plasma free haemoglobin, white cell count and ECMO flow rate on concordance between APR and N-ACT measurements.
Results:
The Pearson product-moment correlation coefficient in 15 patients was calculated as r=0.55. The Bland-Altman plot shows a mean difference between the APR and the N-ACT of −0.08. The 95% limits of agreement were −0.67 to 0.51. Results from mixed effects regression analysis on data from the 15 patients identified platelet count (and thrombocytopenia) and urea as significant independent predictors of concordance between APR and N-ACT.
Conclusion:
We report a moderate degree of positive correlation between APR and N-ACT. We conclude that there is poor agreement between the ACT and aPTT for the heparin concentrations in patients supported with ECMO. Our results indicate that platelet count and urea are significant independent variables affecting concordance between ACT and aPTT measurements.
The coagulopathy of cardiopulmonary bypass Besser, Martin W.; Klein, Andrew A.
Critical reviews in clinical laboratory sciences,
12/2010, Letnik:
47, Številka:
5-6
Journal Article
Recenzirano
There have been numerous publications on the coagulopathy of cardiopulmonary bypass (CPB). This review provides an introduction to the history and main components of current CPB circuits and ...summarizes the current knowledge of pathogenesis, prevention, and treatment of the CPB coagulopathy. It encompasses an overview of intra- and postoperative monitoring of coagulation with special emphasis on the near-patient testing, its main complications, and the transfusion support, while taking into account the major changes in the technology used and supportive care provided since its inception.
The differential diagnosis between iron deficiency anaemia (IDA) and anaemia of chronic disease (ACD) with or without associated iron deficiency can be challenging. We assessed the use of different ...parameters, both classical like ferritin, transferrin saturation and stainable bone marrow iron stores, and novel markers such as low haemoglobin density (LHD) and hepcidin to help discriminate between the three entities. This would allow the detection of patients with ACD with associated iron deficiency, which could benefit from iron supplementation that would have otherwise remained undetected.
Prospective and observational cohort study from 2012 to 2013 where 200 anaemic cardiac surgical patients were recruited and 165 were studied. Detailed blood and bone marrow analyses were performed to establish the aetiology of anaemia.
Seventy-four patients (44.8%) had ACD and 29 (39%) of these had an elevated LHD indicating concomitant iron deficiency. Hepcidin was inappropriately normal or increased in the IDA and ACD group. Mean hepcidin was however lower in the group with IDA (4.8 ng/mL) than in the ACD group (15.0 ng/mL; p=0.002). Median hepcidin was lower in patients with ACD and iron restriction as indicated by LHD >4% (17.5 ng/mL) than on those with no iron restriction (25.9 ng/mL; p=0.045). In patients with ACD there was no concordance between Perl's stain and LHD.
LHD was superior to hepcidin and bone marrow iron stores in identifying patients with ACD and associated iron deficiency, which would potentially benefit from parenteral iron therapy.
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