Isohemagglutinin titration in pooled and apheresis platelets.

BACKGROUND: Platelet inventory constraints necessitate ABO-incompatible platelet transfusion. Many minimize the hemolytic impact by confirming low titre (LT) donor isohemagglutinins. This process is costly. Pathogen-reduced platelets (PRP) in platelet additive solutions (PAS) will dilute plasma and decrease high-titre isohemagglutinins (HT). We determined the proportion of HT platelets and incompatible transfusions for units suspended in plasma to reassess the need for titres following introduction of PRP/PAS. STUDY DESIGN AND METHODS: Our titre method is manual tube (1:50) dilution of platelet supernatant from apheresis or whole blood derived buffy coat pools suspended in plasma, tested with A1/B red cells. Testing included 49,058 pooled and 11,738 apheresis platelets over 4 years. The HT proportion, rate of out-of-group transfusions, and hemolytic reactions were determined. The impact of PAS dilution was estimated. RESULTS: Totally 60,796 platelet units were tested. Group O pooled and group B apheresis platelets had HT in 6.6% and 5.7%, respectively. Group A pooled and apheresis platelets included 2% with HT. Approximately 25% of platelets transfused were ABO-incompatible and no hemolytic reactions were reported. Based on the proportions of PAS-E and plasma for PRP platelets, plasma from each donor comprises 11 mL (6% of total volume) vs 20-257 mL in untreated pools. PAS-E will replace and dilute residual plasma by at least 50%. DISCUSSION: Rare platelet pools may demonstrate HT. PRP platelets with PAS will reduce titres and may abrogate the need for titration. A strategy of group specific transfusion or transfusion of group A PRP platelet transfusions may be a safe alternative.

How do we achieve blinding in modern electronic and paper medical records during the conduct of transfusion trials?

BACKGROUND: Regulatory aspects of transfusion medicine add complexity in blinded transfusion trials when considering various electronic record keeping software and blood administration processes. The aim of this study is to explore strategies when blinding transfusion components and products in paper and electronic medical records. METHODS: Surveys were collected and interviews were conducted for 18 sites across various jurisdictions in North America to determine solutions applied in previous transfusion randomized control trials. RESULTS: Sixteen responses were collected of which 11 had previously participated in a transfusion randomized control trial. Various solutions were reported which were specific to the laboratory information system (LIS) and electronic medical record (EMR) combinations although solutions could be grouped into four categories which included the creation of a study product code in the LIS, preventing the transmission of data from the LIS to the EMR, utilizing specialized stickers and labels to conceal product containers and documents in the paper records, and modified bedside procedures and documentation. DISCUSSION: LIS and EMR combinations varied across sites, so it was not possible to determine combination-specific solutions. The study was able to highlight solutions that may be emphasized in future iterations of LIS and EMR software as well as procedural changes that may minimize the risk of unblinding.

Canadian Blood Services traceback investigation of a suspected case of transfusion-transmitted malaria.

BACKGROUND: A 4-month-old infant hospitalized since birth received multiple blood transfusions. In March 2022, Plasmodium falciparum was confirmed with nucleic acid testing. As the mother was assessed as unlikely to be the source of infection, the blood operator initiated a traceback investigation for a potential blood donor source. The patient had received 13 red blood cell (RBC) transfusions (aliquoted from 11 donors), 4 apheresis platelet (PLT) transfusions and 16 buffy coat pooled PLT transfusions. The blood operator medical team developed a supplementary malaria infection risk questionnaire to identify donors at highest risk of life-time malaria infection, based on birthplace, residence, or travel in malaria-endemic regions. RESULTS: With 79 donors initially implicated, initial focus was on donors of RBC components. The 11 RBC donors were contacted and assessed using the supplementary questionnaire. Three donors, all of whom met current malaria-related donor eligibility criteria, were deemed high risk of prior malaria infection. These donors consented to P. falciparum serology and nucleic acid testing (NAT). One donor who was born and had resided in an endemic West African country for 14 years, was positive for P. falciparum by serology (indirect fluorescent antibody test) and NAT-(Ct ≥32). Lookback of this donor's transfused fresh co-components and prior donation identified no other malaria cases. CONCLUSION: This was a probable transfusion-transmitted malaria (TTM) case from an eligible donor who in retrospect was found to have unrecognized, asymptomatic, semi-immune malaria infection, and who was potentially infectious. Blood donor lack of recall of prior malaria infection does not negate the risk of TTM from those who have lived in malaria-endemic countries.

Systematic reviews on platelet transfusions: Is there unnecessary duplication of effort? A scoping review.

BACKGROUND AND OBJECTIVES: Platelet transfusions are used across multiple patient populations to prevent and correct bleeding. This scoping review aimed to map the currently available systematic reviews (SRs) and evidence-based guidelines in the field of platelet transfusion. MATERIALS AND METHODS: A systematic literature search was conducted in seven databases for SRs on effectiveness (including dose and timing, transfusion trigger and ratio to other blood products), production modalities and decision support related to platelet transfusion. The following data were charted: methodological features of the SR, population, concept and context features, outcomes reported, study design and number of studies included. Results were synthesized in interactive evidence maps. RESULTS: We identified 110 SRs. The majority focused on clinical effectiveness, including prophylactic or therapeutic transfusions compared to no platelet transfusion (34 SRs), prophylactic compared to therapeutic-only transfusion (8 SRs), dose, timing (11 SRs) and threshold for platelet transfusion (15 SRs) and the ratio of platelet transfusion to other blood products in massive transfusion (14 SRs). Furthermore, we included 34 SRs on decision support, of which 26 evaluated viscoelastic testing. Finally, we identified 22 SRs on platelet production modalities, including derivation (4 SRs), pathogen inactivation (6 SRs), leucodepletion (4 SRs) and ABO/human leucocyte antigen matching (5 SRs). The SRs were mapped according to concept and clinical context. CONCLUSION: An interactive evidence map of SRs and evidence-based guidelines in the field of platelet transfusion has been developed and identified multiple reviews. This work serves as a tool for researchers looking for evidence gaps, thereby both supporting research and avoiding unnecessary duplication.

Current state of technical transfusion medicine practice for out-of-hospital blood transfusion in Canada.

BACKGROUND AND OBJECTIVES: Canadian out-of-hospital blood transfusion programmes (OHBTPs) are emerging, to improve outcomes of trauma patients by providing pre-hospital transfusion from the scene of injury, given prolonged transport times. Literature is lacking to guide its implementation. Thus, we sought to gather technical transfusion medicine (TM)-specific practices across Canadian OHBTPs. MATERIALS AND METHODS: A survey was sent to TM representatives of Canadian OHBTPs from November 2021 to March 2022. Data regarding transport, packaging, blood components and inventory management were included and reported descriptively. Only practices involving Blood on Board programme components for emergency use were included. RESULTS: OHBTPs focus on helicopter emergency medical service programmes, with some supplying fixed-wing aircraft and ground ambulances. All provide 1-3 coolers with 2 units of O RhD/Kell-negative red blood cells (RBCs) per cooler, with British Columbia trialling coolers with 2 units of pre-thawed group A plasma. Inventory exchanges are scheduled and blood components are returned to TM inventory using visual inspection and internal temperature data logger readings. Coolers are validated to storage durations ranging from 72 to 124 h. All programmes audit to manage wastage, though there is no consensus on appropriate benchmarks. All programmes have a process for documenting units issued, reconciliation after transfusion and for transfusion reaction reporting; however, training programmes vary. Common considerations included storage during extreme temperature environments, O-negative RBC stewardship, recipient notification, traceability, clinical practice guidelines co-reviewed by TM and a common audit framework. CONCLUSION: OHBTPs have many similarities throughout Canada, where harmonization may assist in further developing standards, leveraging best practice and national coordination.

International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn.

Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.

International Society of Blood Transfusion survey of experiences of blood banks and transfusion services during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has impacted blood systems worldwide. Challenges included maintaining blood supplies and initiating the collection and use of COVID-19 convalescent plasma (CCP). Sharing information on the challenges can help improve blood collection and utilization. MATERIALS AND METHODS: A survey questionnaire was distributed to International Society of Blood Transfusion members in 95 countries. We recorded respondents' demographic information, impacts on the blood supply, CCP collection and use, transfusion demands and operational challenges. RESULTS: Eighty-two responses from 42 countries, including 24 low- and middle-income countries, were analysed. Participants worked in national (26.8%) and regional (26.8%) blood establishments and hospital-based (42.7%) institutions. CCP collection and transfusion were reported by 63% and 36.6% of respondents, respectively. Decreases in blood donations occurred in 70.6% of collecting facilities. Despite safety measures and recruitment strategies, donor fear and refusal of institutions to host blood drives were major contributing factors. Almost half of respondents working at transfusion medicine services were from large hospitals with over 10,000 red cell transfusions per year, and 76.8% of those hospitals experienced blood shortages. Practices varied in accepting donors for blood or CCP donations after a history of COVID-19 infection, CCP transfusion, or vaccination. Operational challenges included loss of staff, increased workloads and delays in reagent supplies. Almost half of the institutions modified their disaster plans during the pandemic. CONCLUSION: The challenges faced by blood systems during the COVID-19 pandemic highlight the need for guidance, harmonization, and strengthening of the preparedness and the capacity of blood systems against future infectious threats.

Quality of evidence-based guidelines for platelet transfusion and use: A systematic review.

BACKGROUND: Guidelines for platelet (PLT) transfusion are an important source of information for clinicians. Although guidelines intend to increase consistency and quality of care, variation in methodology and recommendations may exist that could impact the value of a guideline. We aimed to determine the quality of existing PLT transfusion guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument and to describe the inconsistencies in recommendations. STUDY DESIGN AND METHODS: A systematic search was undertaken for evidence-based guidelines from January 1, 2013, to January 25, 2019. Citations were reviewed in duplicate for inclusion and descriptive data extracted. Four physicians appraised the guideline using the AGREE II instrument and the scaled score for each item evaluated was calculated. The protocol was registered in PROSPERO. RESULTS: Of 6744 citations, 6740 records were screened. Seven of 28 full-text studies met the inclusion criteria. The median scaled score (and the interquartile range of the scaled score) for the following items were as follows: scope and purpose, 94% (8%); stakeholder involvement, 63% (18%); rigor of development, 83% (14%); clarity of presentation, 94% (6%); applicability, 58% (20%); and editorial independence, 77% (4%). Overall quality ranged from 4 to 7 (7 is the maximum score). Inconsistent recommendations were on prophylactic PLT transfusion in hypoproliferative thrombocytopenia in the presence of risk factors and dose recommendations. CONCLUSION: Inconsistencies between guidelines and variable quality highlight areas for future guideline writers to address. Areas of specific attention include issues of stakeholder involvement and applicability.

Hypothermic storage of leukoreduced red blood cells for greater than 21 days is a safe alternative to irradiation.

BACKGROUND: Irradiation of red blood cells (RBCs) inactivates residual donor T lymphocytes to prevent transfusion-associated graft-vs-host disease (TA-GVHD) but can have adverse effects on recipients and inventory management. Reported incidence of TA-GVHD is lower when leukoreduced RBCs and older blood products are transfused; therefore, the impact of leukoreduction and storage was evaluated as an alternative prevention strategy. STUDY DESIGN AND METHODS: Effectiveness of leukoreduction filters on white blood cell (WBC) proliferation was evaluated by filtering buffy coat (BC) products and isolating residual WBCs. Additionally, leukoreduced RBCs were spiked with 5 × 106 WBCs on Day 21 of hypothermic storage, then stored and processed on Days 7, 14, and 21 to obtain residual WBCs to investigate the impact of hypothermic storage on their viability and proliferative ability. Viability of residual WBCs was assessed by staining with annexin V and an antibody cocktail for flow cytometry analysis. Proliferative ability was assessed by placing carboxyfluorescein diacetate succinimidyl ester-labeled residual WBCs into culture for 6 days with phytohemagglutinin before flow cytometry assessment. RESULTS: Filtration of BC units depleted WBCs, particularly T lymphocytes, to 0.001% ± 0.003% cells/unit, although proliferative activity remained consistent with prefiltration levels of WBCs. WBCs in stored RBCs remained viable even on Day 21 of storage; however, the proliferative activity decreased to 0.24% ± 0.41%. CONCLUSIONS: Hypothermic storage of RBCs for 21 days or more is sufficient to inactivate T lymphocytes, which may help prevent TA-GVHD when irradiated RBCs are not available.

A prospective multi-faceted interventional study of blood bank technologist screening of red blood cell transfusion orders: The START study.

BACKGROUND: Transfusion of red blood cells (RBC) is a common procedure, which when prescribed inappropriately can result in adverse patient outcomes. This study sought to determine the impact of a multi-faceted intervention on unnecessary RBC transfusions at hospitals with a baseline appropriateness below 90%. STUDY DESIGN AND METHODS: A prospective medical chart audit of RBC transfusions was conducted across 15 hospitals. For each site, 10 RBCs per month transfused to inpatients were audited for a 5-month pre- and 10-month post-intervention period, with each transfusion adjudicated for appropriateness based on pre-set criteria. Hospitals with appropriateness rates below 90% underwent a 3-month intervention which included: adoption of standardized RBC guidelines, staff education, and prospective transfusion order screening by blood bank technologists. Proportions of RBC transfusions adjudicated as appropriate and the total number of RBC units transfused per month in the pre- and post-intervention period were examined. RESULTS: Over the 15-month audit period, at the 13 hospital sites with a baseline appropriateness below 90%, 1950 patients were audited of which 81.2% were adjudicated as appropriate. Proportions of appropriateness and single-unit orders increased from 73.5% to 85% and 46.2% to 68.2%, respectively from pre- to post-intervention (P < .0001). Pre- and post-transfusion hemoglobin levels and the total number of RBCs transfused decreased from baseline (P < .05). The median pre-transfusion hemoglobin decreased from a baseline of 72.0 g/L to 69.0 g/L in the post-intervention period (P < .0001). RBC transfusions per acute inpatient days decreased significantly in intervention hospitals, but not in control hospitals (P < .001). The intervention had no impact on patient length of stay, need for intensive care support, or in-hospital mortality. CONCLUSION: This multifaceted intervention demonstrated a marked improvement in RBC transfusion appropriateness and reduced overall RBC utilization without impacts on patient safety.

Transfusion-transmitted and community-acquired cytomegalovirus infection in seronegative solid organ transplant recipients receiving seronegative donor organs.

Solid organ transplant (SOT) recipients who are cytomegalovirus (CMV) seronegative (R-) and receive seronegative donor (D-) organs have a small but currently unquantified risk of both transfusion-transmitted CMV (TT-CMV) and community-acquired CMV (CA-CMV). We retrospectively studied the incidence and clinical symptoms of TT-CMV (infection <1 year posttransplant) and CA-CMV (infection >1 year posttransplant) in a cohort of D-/R- adult and pediatric SOT recipients receiving leukoreduced blood products not screened for CMV seronegativity transplanted at our center between 2000 and 2011. CMV infection was defined as IgG seroconversion or detectable CMV antigenemia/DNAemia. Among 536 consecutive D-/R- recipients, 398 (81.8%) had adequate follow-up, and 231 (58%) received cellular blood products (total: 1626 red blood cell units, 470 platelet units) 30 days pretransplant to 90 days posttransplant. We observed no confirmed TT-CMV cases, but 14 CA-CMV cases (64% symptomatic) were seen. The estimated incidence rate of CA-CMV was higher in children (3.0/100 patient years) than adults (0.46/100 patient years, incident rate ratio of 6.52). The absence of TT-CMV over 11 years suggests neither seronegative blood products nor CMV DNA blood donor screening would provide significant incremental safety when blood is already leukoreduced. D-/R- SOT recipients, particularly children, have a significantly higher and ongoing risk of CA-CMV.

Albumin 5% Versus Crystalloids for Fluid Resuscitation in Children After Cardiac Surgery.

OBJECTIVES: To determine the clinical benefit of using colloids versus crystalloids for volume resuscitation in children admitted after cardiac surgery. DESIGN: Retrospective pre-/postintervention cohort study. SETTING: Stollery Children's Hospital tertiary care pediatric cardiac ICU. PATIENTS: Children admitted to the pediatric cardiac ICU after cardiac surgery. INTERVENTIONS: Fluid resuscitation policy change in which crystalloids replaced albumin 5% as the primary fluid strategy for resuscitation after cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Children who underwent cardiac surgery in the 6 months prior to the policy change (5% albumin group) were compared with children admitted during the 6 months after (crystalloid group). Demographic, perioperative, and outcome variables (fluid intake days 1-4 postoperative, vasoactive therapy, blood products, time to negative fluid balance, renal replacement therapies, mechanical ventilation, pediatric cardiac ICU, and length of stay) were collected. Data were analyzed using linear and logistic multivariate analysis. The study included 360 children. There was no association between fluid group and fluid intake (mL/kg) on day 1 postoperatively (coefficient, 2.84; 95% CI, 5.37-11.05; p = 0.497). However, crystalloid group was associated with significantly less fluid intake on day 2 (coefficient, -12.8; 95% CI, -22.0 to -3.65; p = 0.006), day 3 (coefficient, -14.9; 95% CI, -24.3 to -5.57; p = 0.002), and on the first 48 hours postoperative (coefficient, 10.1; 95% CI, -27.9 to -1.29; p = 0.032). Pediatric cardiac ICU stay (coefficient, -1.29; 95% CI, -2.50 to -0.08; p = 0.036) was shorter for the crystalloid group. There were no significant differences in the time to negative balance, need for renal replacement therapy, mechanical ventilation days, hospital stay, or pediatric cardiac ICU survival. CONCLUSIONS: In our study, the use of albumin 5% for resuscitation after cardiac surgery was not associated with less fluid intake but rather the opposite. Albumin administration did not provide measured clinical benefit while exposing children to side effects and generating higher costs to the healthcare system.

Two cases of the variant RHD*DAU5 allele associated with maternal alloanti-D.

CONCLUSIONS: Rh is a complex blood group system with diverse genotypes that may encode weak and partial D variants. Standard serologic analysis may identify clinically significant D variants as D+; nevertheless, individuals with these D variants should be managed as D- patients to prevent antibody formation to absent D epitopes. Variant identification is necessary during pregnancy to allow for timely and appropriate Rh immune globulin (RhIG) prophylaxis for hemolytic disease of the fetus and newborn (HDFN) as D alloimmunization can occur with some D variants. Here, we describe two cases of the RHD*DAU5 allele associated with maternal alloanti-D in patients of African ancestry. Two obstetric patients were initially serologically classified as D+ with negative antibody detection tests on routine prenatal testing. Repeat testing at delivery identified anti-D in both patients with no history of RhIG administration or transfusion. DNA sequencing revealed that both patients possessed the RHD*DAU5 allele. Cord blood testing on both infants revealed positive direct antiglobulin test (DAT) results with anti-D eluted from the red blood cells (RBCs) of one of the infants. Despite the positive DAT, neither infant experienced anemia or hyperbilirubinemia. We document two cases of pregnant women whose RBCs expressed a partial D variant and were classified as D+ on the basis of standard serologic testing, resulting in subsequent failure to provide RhIG prophylaxis. Both cases were associated with alloanti-D formation but without significant HDFN. To our knowledge, these are the first reported cases of maternal alloanti-D associated with the RHD*DAU5 partial D variant.

Common bleeding disorders affecting individuals with Hereditary Hemorrhagic Telangiectasia.

PURPOSE: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder affecting vasculature in different organ systems; seen at a rate of approximately 1:5000 in North America. Complications, with significant increases in health service utilization, arise from bleeding and shunts, and are particularly problematic in the lung and liver. Although these patients tend to chronically bleed from the GI tract and nasal cavities, a single bleed from arterio-venous malformations in the lungs or brain can have serious health implications and may be fatal. Bleeding due to vascular wall fragility in HHT patients can be further complicated with a concomitant bleeding disorder. METHODS: The proportion of adult patients seen in the Edmonton HHT center with a concomitant bleeding disorder, as assessed by blood test results for Factor VIII and related factors (Ristocetin Cofactor), Factor IX and Factor XI, was determined in a retrospective, single centre study. RESULTS: Of 77 individuals with HHT, four had below normal values of von Willebrand Factor, Ristocetin Cofactor or Factor VIII. Two patients had laboratory parameters diagnostic of a bleeding disorder, accounting for 2.6% of confirmed HHT subjects. These results indicate that establishing screening for bleeding disorders in HHT centers is important in managing bleeding symptomatology. CONCLUSIONS: In individuals with HHT, the presence of a second bleeding disorder can have significant clinical implications on patient management and health care utilizations. This paper highlights areas that need to be reviewed with respect to best practice protocols for the management of HHT patients.

Bedside to bench: The risk of bleeding with parenteral omega-3 lipid emulsion therapy.

Our clinical experience led us to reassess the effect of sole omega-3 lipid therapy on hemostasis. We compared thromboelastography platelet mapping in neonatal piglets given sole omega-3 lipid. We identified abnormalities in reaction time (P = .025) and the arachidonic acid pathway (P = .025). The potential for bleeding complications from parenteral omega-3 lipid emulsion therapy in high-risk infants with liver disease has been dismissed but, on the basis of this data, should be reconsidered.

Transfusion-related acute lung injury after transfusion of pooled immune globulin: a case report.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a severe transfusion reaction that manifests as acute respiratory compromise within 6 hours of the infusion of blood products. Intravenous immune globulin (IVIG) is prepared from large pools of human plasma and is commonly administered in the outpatient setting for the treatment of a wide range of diseases. As a plasma-derived blood product, IVIG may also cause TRALI, although reports of this are exceedingly rare. CASE REPORT: A 77-year-old female with common variable immune deficiency had been receiving IVIG since 1996 for infection prophylaxis. During a scheduled infusion, the patient developed hypertension and dyspnea, requiring increasing oxygen supplementation and subsequent intubation. Radiographic studies demonstrated the bilateral chest infiltrates, with no evidence of infection or circulatory overload. The patient was extubated after 24 hours and discharged several days later. The patient had not previously received this lot of IVIG and has since received further transfusions with different lot numbers of the same product without incident. CONCLUSION: This case report documents a case of TRALI after IVIG transfusion. While a very rare cause, this case furthers evidence that TRALI can occur after IVIG transfusion.

Cost-Effectiveness of Thrombopoietin Mimetics in Patients with Thrombocytopenia: A Systematic Review.

OBJECTIVES: Thrombopoietin (TPO) mimetics are a potential alternative to platelet transfusion to minimize blood loss in patients with thrombocytopenia. This systematic review aimed to evaluate the cost-effectiveness of TPO mimetics, compared with not using TPO mimetics, in adult patients with thrombocytopenia. METHODS: Eight databases and registries were searched for full economic evaluations (EEs) and randomized controlled trials (RCTs). Incremental cost-effectiveness ratios (ICERs) were synthesized as cost per quality-adjusted life year gained (QALY) or as cost per health outcome (e.g. bleeding event avoided). Included studies were critically appraised using the Philips reporting checklist. RESULTS: Eighteen evaluations from nine different countries were included, evaluating the cost-effectiveness of TPO mimetics compared with no TPO, watch-and-rescue therapy, the standard of care, rituximab, splenectomy or platelet transfusion. ICERs varied from a dominant strategy (i.e. cost-saving and more effective), to an incremental cost per QALY/health outcome of EUR 25,000-50,000, EUR 75,000-750,000 and EUR > 1 million, to a dominated strategy (cost-increasing and less effective). Few evaluations (n = 2, 10%) addressed the four principal types of uncertainty (methodological, structural, heterogeneity and parameter). Parameter uncertainty was most frequently reported (80%), followed by heterogeneity (45%), structural uncertainty (43%) and methodological uncertainty (28%). CONCLUSIONS: Cost-effectiveness of TPO mimetics in adult patients with thrombocytopenia ranged from a dominant strategy to a significant incremental cost per QALY/health outcome or a strategy that is clinically inferior and has increased costs. Future validation and tackling the uncertainty of these models with country-specific cost data and up-to-date efficacy and safety data are needed to increase the generalizability.