Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial damage syndrome that is increasingly identified as a complication of both autologous and allogeneic hematopoietic cell transplantation (HCT) in children. If not promptly diagnosed and treated, TA-TMA can lead to significant morbidity (e.g., permanent renal injury) or mortality. However, as the recognition of the early stages of TA-TMA may be difficult, we propose a TA-TMA "triad" of hypertension, thrombocytopenia (or platelet transfusion refractoriness), and elevated lactate dehydrogenase (LDH). While not diagnostic, this triad should prompt further evaluation for TA-TMA. There is increased understanding of the risk factors for the development of TA-TMA, including those which are inherent (e.g., race, genetics), transplant approach-related (e.g., second HCT, use of HLA-mismatched donors), and related to post-transplant events (e.g., receipt of calcineurin inhibitors, development of graft-vs. -host-disease, or certain infections). This understanding should lead to enhanced screening for TA-TMA signs and symptoms in high-risk patients. The pathophysiology of TA-TMA is complex, resulting from a cycle of activation of endothelial cells to produce a pro-coagulant state, along with activation of antigen-presenting cells and lymphocytes, as well as activation of the complement cascade and microthrombi formation. This has led to the formulation of a "Three-Hit Hypothesis" in which patients with either an underlying predisposition to complement activation or pre-existing endothelial injury (Hit 1) undergo a toxic conditioning regimen causing endothelial injury (Hit 2), and then additional insults are triggered by medications, alloreactivity, infections, and/or antibodies (Hit 3). Understanding this cycle of injury permits the development of a specific TA-TMA treatment algorithm designed to treat both the triggers and the drivers of the endothelial injury. Finally, several intriguing approaches to TA-TMA prophylaxis have been identified. Future work on the development of a single diagnostic test with high specificity and sensitivity, and the development of a robust risk-scoring system, will further improve the management of this serious post-transplant complication.

/pdf/transplant-associated-thrombotic-microangiopathy-in-370bwak44g.pdf

Transplant-Associated Thrombotic Microangiopathy in Pediatric Hematopoietic Cell Transplant Recipients: A Practical Approach to Diagnosis and Management.

NHS Blood and Transplant Cambridge, Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, Department of Haematology, Royal Devon & Exeter NHS Foundation Trust, Exeter, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, Serious Hazards of Transfusion Office, Manchester Blood Centre, Haematology, University of Cambridge, Cambridge Biomedical Campus, Clinical Neuroscience, University of Cambridge, Cambridge Biomedical Campus, Department of Paediatric Immunology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, Department of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, NHS Blood and Transplant, London, Department of Haematology, Imperial College London, and Department of Clinical Nephrology and Transplantation, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjh.17015

Guidelines on the use of irradiated blood components.

Transfusion-related adverse reactions: Data from the National Healthcare Safety Network Hemovigilance Module — United States, 2013–2018

Aim The aim of the current review was to outline the existing information related to antimicrobial properties of various platelet concentrates, as experimented in various in-vitro studies. Background One of the most interesting recent landmarks in the field of biological therapy has been the discovery that platelets, in addition to being capable of releasing hundreds of proteins and growth factors, can also release immunomodulatory agents with antimicrobial activity. Several international research groups have reported antimicrobial activities in both human platelets and other types of platelet rich plasma preparations. Review Result This review was carried-out pursuing a systematic approach. An electronic search was conducted on MEDLINE and GOOGLE SCHOLAR databases using suitable search terminologies. It included preclinical studies which assessed the antimicrobial activity of Autologous Platelet Concentrates(APC).Ten in-vitro studies and one animal study, which investigated APC effects on various microorganisms, were included. Almost in all the included in-vitro studies, it was found that complete breakdown of microbial load could not be achieved by any of the APC preparations but there occurred a reduction in the growth of microorganisms. Thus APCs displayed a bacteriostatic rather than bacteriocidal activity.The only animal study included in this review which had both in-vitro and in-vivo evaluation, also showed reduction of infection caused by different microorganisms. Conclusion Although the precise mechanism of synergy with microbial pathogens needs further validation, platelet concentrates proved to have antimicrobial properties.

Antimicrobial effects of various platelet rich concentrates-vibes from in-vitro studies-a systematic review.

Complement is one of the most ancient defense systems. It gets strongly activated immediately after acute injuries like trauma, burn, or sepsis and helps to initiate regeneration. However, uncontrolled complement activation contributes to disease progression instead of supporting healing. Such effects are perceptible not only at the site of injury but also systemically, leading to systemic activation of other intravascular cascade systems eventually causing dysfunction of several vital organs. Understanding the complement pathomechanism and its interplay with other systems is a strict requirement for exploring novel therapeutic intervention routes. Ex vivo models exploring the cross-talk with other systems are rather limited, which complicates the determination of the exact pathophysiological roles that complement has in trauma, burn, and sepsis. Literature reporting on these three conditions is often controversial regarding the importance, distribution, and temporal occurrence of complement activation products further hampering the deduction of defined pathophysiological pathways driven by complement. Nevertheless, many in vitro experiments and animal models have shown beneficial effects of complement inhibition at different levels of the cascade. In the future, not only inhibition but also a complement reconstitution therapy should be considered in prospective studies to expedite how meaningful complement-targeted interventions need to be tailored to prevent complement augmented multi-organ failure after trauma, burn, and sepsis. This review summarizes clinically relevant studies investigating the role of complement in the acute diseases trauma, burn, and sepsis with important implications for clinical translation.

/pdf/complement-as-driver-of-systemic-inflammation-and-organ-2q8yedotot.pdf

Complement as driver of systemic inflammation and organ failure in trauma, burn, and sepsis.

Increased complement activation during platelet storage.

BACKGROUND Platelets (PLTs) have been associated with the highest rate of transfusion-associated adverse events (AEs) among all blood products. Most of PLT-associated AEs are considered to have an inflammatory mechanism. However, it is still unclear whether prolonged storage of platelets is associated with an increased rate of transfusion-related AEs, especially in the era of universal prestorage leucoreduction. METHODS/MATERIALS In this retrospective study, 52 649 PLT products consisting of about 80% apheresis PLTs and 20% whole blood-derived (WBD) PLTs were transfused to 9415 patients from July 2011 to March 2017. All the PLTs were leucoreduced prior to storage. All but 69 units of the apheresis PLTs were irradiated and none of WBD PLTs were irradiated. During this period, a total of 284 AEs that were reported to the transfusion service were analysed. RESULTS Univariate and multivariate logistic analyses showed that apheresis/irradiated PLTs and PLT age were associated with a significantly increased frequency of inflammation type AEs (OR (95% CI): 2·24 (1·32, 4·15) and 1·30 (1·12, 1·52), respectively). There was a significant increase in the frequency of inflammation AEs associated with prolonged storage of apheresis/irradiated PLTs [OR (95% CI): 1·26 (1·03, 1·53)]. In contrast, there was no association between allergic symptoms and PLT age. Moreover, the frequency of transfusion AEs associated with apheresis/irradiated PLTs (57·2/10 000) was significantly higher than that of WBD/nonirradiated PLTs (26·0/10 000) (P < 0·01). CONCLUSION Prolonged storage of apheresis/irradiated PLTs was associated with a higher frequency of inflammation AEs. Apheresis/irradiated PLTs caused more AEs than WBD/nonirradiated PLTs.

Prolonged platelet storage associated with increased frequency of transfusion-related adverse events.

Introduction Rotational thromboelastometry (ROTEM) is increasingly used as a tool for monitoring coagulation status. However, ROTEM is susceptible to misinterpretation due to particular coagulation abnormalities. Here, we report the effects of lupus anticoagulant (LA) on ROTEM. Methods A prospective observational analysis was performed on 16 children with prior studies indicating the presence of LA or antiphospholipid antibodies. ROTEM analysis was performed, and samples were further analyzed by adding phospholipids (PL) to repeat ROTEM analysis if clotting time (CT) abnormalities were discovered with comparison to ROTEM using an equal volume of isotonic saline. Prothrombin time (PT), activated partial thromboplastin time (APTT), dilute Russell's viper venom test (DRVVT), hexagonal phase phospholipid neutralization test (StaClot LA), and factor II activity studies were additionally performed. Results Eighteen samples were analyzed by ROTEM. Prolonged CT on INTEM and EXTEM was observed for 11 samples. Samples with CT prolongation had high DRVVT ratios and prolonged APTT. Further, the addition of PL partially reversed this effect, demonstrating PL-dependent inhibition as the cause of CT prolongation. No factor II deficiencies were identified, excluding LA hypoprothrombinemia syndrome as a cause of these findings. Conclusion Strongly positive LA can prolong the CT on ROTEM studies and lead to erroneous conclusions regarding coagulation status in this patient population.

Does rotational thromboelastometry accurately predict coagulation status in patients with lupus anticoagulant

BACKGROUND Red blood cell (RBC) transfusion is associated with the most transfusion-related adverse events (AE). Recent clinical studies showed no significant difference in transfusion-associated mortality between fresh and older RBCs. However, the impact of storage duration as well as irradiation on nonfatal yet much more common complications has not been fully investigated. MATERIALS/METHODS In this retrospective study of RBC transfusion-associated AEs, a total of 188,562 units of leucocyte-reduced RBCs were transfused in approximately 5·5 years. After excluding washed, deglycerolized, autologous or directed RBCs and RBCs transfused during a massive transfusion protocol, 149,052 units were analysed. Attributes of RBCs including storage time, collection method, CMV serological status and gamma irradiation, as well as the recipient's gender, were analysed. A total of 358 RBC transfusion AEs were categorized into allergic and non-allergic reactions and analysed. RESULTS Univariate and multivariate logistic analyses showed that irradiated RBCs were associated with a significantly increased frequency of non-allergic reactions (OR (95% CI): 1·89 (1·52, 2·35); P < 0·001). There was a significant association between the frequency of non-allergic reactions and the storage time of irradiated RBCs (OR (95% CI): 1·024 (1·001, 1·048); P = 0·042). In contrast, there was no association between the frequency of allergic reactions and the storage time of irradiated RBCs or between the age of non-irradiated RBCs and the frequency of non-allergic reactions. CONCLUSIONS Prolonged storage of irradiated RBCs was associated with a significant increase in non-allergic transfusion reactions. Overall, the irradiated RBCs appeared to cause more non-allergic reactions compared with non-irradiated RBCs.

Irradiation and prolonged storage of red cells are associated with increased adverse events.

Coagulation testing is essential for the diagnosis and management of a variety of hemophilia, thrombophilia, and complicated coagulopathies. This is often used prior to surgery, or as a follow-up investigation for patients being scrutinized for bleeding diathesis, or to monitor the anticoagulant therapy. When the results are abnormal, a mixing study is often the initial reflexive test that can provide valuable information to conclude the assessment, or help guide further investigations. If the mixing “corrects” the test results, a factor deficiency would be suspected. Otherwise, the presence of an inhibitor would be more likely. However, defining “correction” remains difficult and controversial. There are several available methods to determine whether a result is corrected. Each method has its own advantages and limitations. It is noteworthy that although a complete correction can be interpreted as factor deficiency, a partial or incomplete correction does not rule out the coexistence of factor deficiency and the presence of a coagulation inhibitor. Hence, caution should be taken in interpreting mixing study results for patients who are taking direct-acting oral anticoagulants. Ideally, mixing study results are interpreted in correlation with the patient’s clinical history, including bleeding or thrombosis history, and the use of anticoagulants. 

Utility and Interpretation of Coagulation Mixing Studies

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