Association between cardiovascular risk factors and intracranial hemorrhage in patients with acute leukemia.

BACKGROUND: Intracranial hemorrhage is seen more frequently in acute leukemia patients compared to the general population. Besides leukemia-related risk factors, also risk factors that are present in the general population might contribute to hemorrhagic complications in leukemia patients. Of those, cardiovascular risk factors leading to chronic vascular damage could modulate the occurrence of intracranial hemorrhage in these patients, as during their disease and treatment acute endothelial damage occurs due to factors like thrombocytopenia and inflammation. OBJECTIVES: Our aim was to explore if cardiovascular risk factors can predict intracranial hemorrhage in acute leukemia patients. METHODS: In a case-control study nested in a cohort of acute leukemia patients, including 17 cases with intracranial hemorrhage and 55 matched control patients without intracranial hemorrhage, data on cardiovascular risk factors were collected for all patients. Analyses were performed via conditional logistic regression. RESULTS: Pre-existing hypertension and ischemic heart disease in the medical history were associated with intracranial hemorrhage, with an incidence rate ratio of 12.9 (95% confidence interval [CI] 1.5 to 109.2) and 12.1 (95% CI 1.3 to110.7), respectively. CONCLUSION: Both pre-existing hypertension and ischemic heart disease seem to be strong predictors of an increased risk for intracranial hemorrhage in leukemia patients.

Thrombocytopenia and the effect of platelet transfusions on the occurrence of intracranial hemorrhage in patients with acute leukemia - a nested case-control study.

We designed a study to describe the incidence of intracranial hemorrhage according to severity and duration of thrombocytopenia and to quantify the associations of platelet transfusions with intracranial hemorrhage in patients with acute leukemia. In this case-control study nested in a cohort of 859 leukemia patients, cases (n = 17) were patients diagnosed with intracranial hemorrhage who were matched with control patients (n = 55). We documented platelet counts and transfusions for seven days before the intracranial hemorrhage in cases and in a "matched" week for control patients. Three measures of platelet count exposure were assessed in four potentially important time periods before hemorrhage. Among these leukemia patients, we observed the cumulative incidence of intracranial hemorrhage of 3.5%. Low platelet counts were, especially in the three to seven days preceding intracranial hemorrhage, associated with the incidence of intracranial hemorrhage, although with wide confidence intervals. Platelet transfusions during the week preceding the hemorrhage were associated with higher incidences of intracranial hemorrhage; rate ratios (95% confidence interval) for one or two platelet transfusions and for more than two transfusions compared with none were 4.04 (0.73 to 22.27) and 8.91 (1.53 to 51.73) respectively. Thus, among acute leukemia patients, the risk of intracranial hemorrhage was higher among patients with low platelet counts and after receiving more platelet transfusions. Especially, the latter is likely due to clinical factors leading to increased transfusion needs.

Ensuring HLA-matched platelet support requires an ethnic diverse donor population.

BACKGROUND: Patients refractory for platelet transfusions benefit from human leukocyte antigen (HLA)-matched platelet transfusions. Differences in ethnic background of patients and donors could hamper the availability of sufficient numbers of HLA-matched donors for all patients. We evaluated our HLA-matched donor program and explored the role of ethnic background of patients related to the number of available donors. METHODS: We performed a cohort study among consecutive patients who received HLA-matched platelet concentrates in the Netherlands between 1994 and 2017. The number of available matched donors was determined per patient. Haplotypes were constructed from genotypes with computer software (PyPop). Based on haplotypes, HaploStats, an algorithm from the National Marrow Donor Program, was used to assess the most likely ethnic background for patients with 5 or fewer and 30 or more donors. RESULTS: HLA typing was available for 19,478 donors in September 2017. A total of 1206 patients received 12,350 HLA-matched transfusions. A median of 83 (interquartile range, 18-266) donors were available per patient. For 95 (10.3%) patients, 5 or fewer donors were available. These patients were more likely to have an African American background, whereas patients with 30 or more donors were more often from Caucasian origin, compared with Caucasian origin for patients with 30 donors. CONCLUSION: Adequate transfusion support could be guaranteed for most but not all refractory patients. More non-Caucasian donors are required to ensure the availability of HLA-matched donors for all patients in the Netherlands.

HLA-matched platelet transfusions are effective only in refractory patients with positive HLA antibody screening.

BACKGROUND: Recipients of platelet transfusions with 1-hour corrected count increments (1hCCIs) of 7.5 or less on two subsequent platelet transfusions with random platelets may benefit from human leukocyte antigen (HLA)-matched platelet concentrates. We aimed to quantify the efficacy of HLA-matched platelets concentrates expressed in 1hCCIs. METHODS: We performed a cohort study among consecutive refractory patients who received HLA-matched platelet concentrates in the Netherlands between 1994 and 2017. We performed mixed-model linear regression comparing 1hCCIs after HLA split-antigen-matched transfusions with 1hCCIs after HLA-mismatched transfusions, adjusted for within-patient correlations. A donor-to-patient match was categorized as a split-match if all donor HLA-A and -B antigens were present in the patient as well; that is, donor and patient were HLA identical or compatible. Subgroup analyses were performed for patients with positive or negative HLA antibody screens. Finally, the additional effect of ABO mismatches on 1hCCIs was investigated. RESULTS: The 1hCCI after an HLA-matched transfusion was 14.09 (95% reference interval, 1.13-29.89). This was 1.94 (95% confidence interval [CI], 0.74-3.15) higher than 1hCCI after HLA-mismatched transfusions. In patients with negative HLA antibody screening tests, HLA matching did not affect 1hCCIs. Conditional on HLA matching, 1hCCIs decreased by 3.70 (95% CI, -5.22 to -2.18) with major ABO mismatches. CONCLUSION: Matched platelet concentrates yielded maximal 1hCCIs, whereas mismatched transfusions still resulted in adequate increments. There is no indication for HLA-matched platelets in patients with negative antibody screens.

The quality of platelet concentrates related to corrected count increment: linking in vitro to in vivo.

BACKGROUND: Storage of platelet concentrates (PCs) results in reduced recovery and survival of transfused platelets (PLTs). Upon storage PLTs develop storage lesion that can be monitored by several laboratory tests. However, correlation of these descriptive tests with corrected count increments (CCIs), a marker frequently used to establish the effectiveness of PLT transfusions, is limited or unknown. This study investigated to what extent a functional test or a combined in vitro rating score improves the correlation of laboratory tests with 1-hour CCI. STUDY DESIGN AND METHODS: PCs were analyzed using six different laboratory tests (n = 123) before transfusion in a prophylactic setting to 74 hematooncologic patients. Linear regression and Spearman correlation were used to determine associations between descriptive (either separately or combined in an in vitro rating score) or functional test results and 1-hour CCIs obtained after transfusion. RESULTS: CD62P expression (r = -0.45), annexin V binding (r = -0.36), the updated in vitro rating score (r = 0.50), and PLT responsiveness after thrombin receptor activator for peptide-6 (TRAP) (r = 0.43-0.57) or adenosine diphosphate stimulation (r = 0.11-0.51) significantly correlated to 1-hour CCIs obtained after transfusion, whereas lactate concentration, ThromboLUX score, and thromboelastography measurements did not. The strongest correlations were observed for in vitro rating score and PLT responsiveness after TRAP stimulation and these tests could explain 24 and 33% of the observed variation in 1-hour CCI, respectively. CONCLUSION: Combining descriptive markers in one in vitro rating score improved correlation to 1-hour CCI compared to the tests separately. Of all tests investigated, mean PLT responsiveness after TRAP stimulation showed the strongest clinical correlation and was best able to predict the 1-hour CCI.

The identification of cases of major hemorrhage during hospitalization in patients with acute leukemia using routinely recorded healthcare data.

INTRODUCTION: Electronic health care data offers the opportunity to study rare events, although detecting these events in large datasets remains difficult. We aimed to develop a model to identify leukemia patients with major hemorrhages within routinely recorded health records. METHODS: The model was developed using routinely recorded health records of a cohort of leukemia patients admitted to an academic hospital in the Netherlands between June 2011 and December 2015. Major hemorrhage was assessed by chart review. The model comprised CT-brain, hemoglobin drop, and transfusion need within 24 hours for which the best discriminating cut off values were taken. External validation was performed within a cohort of two other academic hospitals. RESULTS: The derivation cohort consisted of 255 patients, 10,638 hospitalization days, of which chart review was performed for 353 days. The incidence of major hemorrhage was 0.22 per 100 days in hospital. The model consisted of CT-brain (yes/no), hemoglobin drop of ≥0.8 g/dl and transfusion of ≥6 units. The C-statistic was 0.988 (CI 0.981-0.995). In the external validation cohort of 436 patients (19,188 days), the incidence of major hemorrhage was 0.46 per 100 hospitalization days and the C-statistic was 0.975 (CI 0.970-0.980). Presence of at least one indicator had a sensitivity of 100% (CI 95.8-100) and a specificity of 90.7% (CI 90.2-91.1). The number of days to screen to find one case decreased from 217.4 to 23.6. INTERPRETATION: A model based on information on CT-brain, hemoglobin drop and need of transfusions can accurately identify cases of major hemorrhage within routinely recorded health records.

Why was this transfusion given? Identifying clinical indications for blood transfusion in health care data.

BACKGROUND: To enhance the utility of transfusion data for research, ideally every transfusion should be linked to a primary clinical indication. In electronic patient records, many diagnostic and procedural codes are registered, but unfortunately, it is usually not specified which one is the reason for transfusion. Therefore, a method is needed to determine the most likely indication for transfusion in an automated way. STUDY DESIGN AND METHODS: An algorithm to identify the most likely transfusion indication was developed and evaluated against a gold standard based on the review of medical records for 234 cases by 2 experts. In a second step, information on misclassification was used to fine-tune the initial algorithm. The adapted algorithm predicts, out of all data available, the most likely indication for transfusion using information on medical specialism, surgical procedures, and diagnosis and procedure dates relative to the transfusion date. RESULTS: The adapted algorithm was able to predict 74.4% of indications in the sample correctly (extrapolated to the full data set 75.5%). A kappa score, which corrects for the number of options to choose from, was found of 0.63. This indicates that the algorithm performs substantially better than chance level. CONCLUSION: It is possible to use an automated algorithm to predict the indication for transfusion in terms of procedures and/or diagnoses. Before implementation of the algorithm in other data sets, the obtained results should be externally validated in an independent hospital data set.

Storage time of platelet concentrates and risk of a positive blood culture: a nationwide cohort study.

BACKGROUND: Concern of transfusion-transmitted bacterial infections has been the major hurdle to extend shelf life of platelet (PLT) concentrates. We aimed to investigate the association between storage time and risk of positive blood cultures at different times after transfusion. STUDY DESIGN AND METHODS: We performed a nationwide cohort study among PLT transfusion recipients in Denmark between 2010 and 2012, as recorded in the Scandinavian Donations and Transfusions (SCANDAT2) database. Linking with a nationwide database on blood cultures (MiBa), we compared the incidence of a positive blood culture among recipients of PLTs stored 6 to 7 days (old) to those receiving fresh PLTs (1-5 days), using Poisson regression models. We considered cumulative exposures in windows of 1, 3, 5, and 7 days. RESULTS: A total of 9776 patients received 66,101 PLT transfusions. The incidence rate ratio (IRR) of a positive blood culture the day after transfusion of at least one old PLT concentrate was 0.77 (95% confidence interval [CI], 0.54-1.09) compared to transfusion of fresh PLT concentrates. The incidence rate of a positive blood culture was lower the day after receiving one old compared to one fresh PLT concentrate (IRR, 0.57; 95% CI, 0.37-0.87). Three, 5, or 7 days after transfusion, storage time was not associated with the risk of a positive blood culture. CONCLUSION: Storage of buffy coat-derived PLT concentrates in PAS-C up to 7 days seems safe regarding the risk of a positive blood culture. If anything, transfusion of a single old PLT concentrate may decrease this risk the following day.

Association of Blood Transfusion From Female Donors With and Without a History of Pregnancy With Mortality Among Male and Female Transfusion Recipients.

Importance: Transfusion of red blood cells from female donors has been associated with increased mortality in male recipients. Objective: To quantify the association between red blood cell transfusion from female donors with and without a history of pregnancy and mortality of red blood cell recipients. Design, Setting, and Participants: Retrospective cohort study of first-time transfusion recipients at 6 major Dutch hospitals enrolled from May 30, 2005, to September 1, 2015; the final follow-up date was September 1, 2015. The primary analysis was the no-donor-mixture cohort (ie, either all red blood cell transfusions exclusively from male donors, or all exclusively from female donors without a history of pregnancy, or all exclusively from female donors with a history of pregnancy). The association between mortality and exposure to transfusions from ever-pregnant or never-pregnant female donors was analyzed using life tables and time-varying Cox proportional hazards models. Exposures: Red blood cell transfusions from ever-pregnant or never-pregnant female donors, compared with red blood cell transfusions from male donors. Main Outcomes and Measures: All-cause mortality during follow-up. Results: The cohort for the primary analyses consisted of 31 118 patients (median age, 65 [interquartile range, 42-77] years; 52% female) who received 59 320 red blood cell transfusions exclusively from 1 of 3 types of donors (88% male; 6% ever-pregnant female; and 6% never-pregnant female). The number of deaths in this cohort was 3969 (13% mortality). For male recipients of red blood cell transfusions, all-cause mortality rates after a red blood cell transfusion from an ever-pregnant female donor vs male donor were 101 vs 80 deaths per 1000 person-years (time-dependent "per transfusion" hazard ratio [HR] for death, 1.13 [95% CI, 1.01-1.26]). For receipt of transfusion from a never-pregnant female donor vs male donor, mortality rates were 78 vs 80 deaths per 1000 person-years (HR, 0.93 [95% CI, 0.81-1.06]). Among female recipients of red blood cell transfusions, mortality rates for an ever-pregnant female donor vs male donor were 74 vs 62 per 1000 person-years (HR, 0.99 [95% CI, 0.87 to 1.13]); for a never-pregnant female donor vs male donor, mortality rates were 74 vs 62 per 1000 person-years (HR, 1.01 [95% CI, 0.88-1.15]). Conclusions and Relevance: Among patients who received red blood cell transfusions, receipt of a transfusion from an ever-pregnant female donor, compared with a male donor, was associated with increased all-cause mortality among male recipients but not among female recipients. Transfusions from never-pregnant female donors were not associated with increased mortality among male or female recipients. Further research is needed to replicate these findings, determine their clinical significance, and identify the underlying mechanism.

Storage time of platelet concentrates and all-cause bacteremia in hematologic patients.

BACKGROUND: Extension of storage time of platelet (PLT) concentrates may result in an increased risk of bacteremia, directly via transfusion of contaminated products or indirectly via transfusion-related immunomodulation. We aimed to quantify the association of storage time of PLT concentrates and all-cause bacteremia in hematologic patients. STUDY DESIGN AND METHODS: We established a cohort of hematologic patients who received a PLT transfusion between 2005 and 2015. Cases were defined as patients with a bacteremia the day after transfusion and matched to as many controls as possible. A conditional logistic regression was performed, stratified by storage medium. RESULTS: Among 3514 patients receiving 36,032 PLT concentrates stored in plasma, 613 cases of bacteremia were found. The relative risk of all-cause bacteremia the day after transfusion was 0.80 (95% confidence interval [CI], 0.58-1.12) for PLT concentrates stored 3 to 4 days and 0.67 (95% CI, 0.49-0.92) for at least 5 days, compared to no more than 2 days. Among 1527 patients receiving 11,822 PLT concentrates stored in PLT additive solution, 182 cases of bacteremia were found. The relative risk of all-cause bacteremia was 1.14 (95% CI, 0.70-1.84) for PLT concentrates stored for 3 to 4 days and 1.19 (95% CI, 0.70-2.01) for at least 5 days, compared to not more than 2 days. CONCLUSION: Storage time of PLT concentrates was not associated with increased occurrence of all-cause bacteremia the day after transfusion. If anything, fewer cases of bacteremia occurred with increasing storage time of PLT concentrates in plasma. These bacteremias are not directly caused by transfusion of a contaminated product and the underlying mechanism warrants further research.

The effect of World Blood Donor Day on digital information seeking and donor recruitment.

BACKGROUND: The purpose of World Blood Donor Day (WBDD) is to raise awareness for the importance of blood donation. The aim of this study was to quantify the impact of WBDD on digital information seeking and donor recruitment. STUDY DESIGN AND METHODS: Google Trends data were used to quantify seeking behavior on "blood donation" and "blood donor." Differences in relative search volume (RSV) between the 3 weeks surrounding WBDD and the rest of the year were calculated. Second, mean differences in RSV were compared to assess the additional effect of hosting using translated search terms. Third, we compared the period around WBDD with the control period regarding page views of the Sanquin website and Facebook likes and number of newly registered donors in 2016. RESULTS: The mean RSV for "blood donation" in the period of interest was 78.6, compared to 72.1 in the control period (difference, 6.5; 95% confidence interval [95% CI], 1.2-11.8). For "blood donor" this was 78.9 compared to 65.9 (difference, 12.9; 95% CI, 8.1-17.8). We found no additional effect of hosting. In the period of interest, the website of Sanquin was visited 6862 times a day and 4293 times in the control period (difference, 2569; 95% CI, 1687-3451). In June 2016, 54.6% (95% CI, 53.0-56.2) more new donors were registered compared to the control period. CONCLUSION: An international campaign like WBDD raises the awareness of blood donation and is effective in convincing people to register as blood donors.

Storage medium of platelet transfusions and the risk of transfusion-transmitted bacterial infections.

BACKGROUND: Transfusion-transmitted bacterial infections (TTBIs) are among the most concerning risks of transfusion of platelet (PLT) concentrates. Storage medium influences bacterial growth dynamics and thereby the sensitivity of screening tests for bacterial contamination. STUDY DESIGN AND METHODS: The aim of this study was to quantify the association of storage media with the incidence of TTBIs after transfusion of PLT concentrates. In the Netherlands, the choice of storage medium is determined solely by geographic location of the hospital. We compared types of storage medium of all reported cases of TTBIs after transfusion of a PLT concentrate with types of storage medium of all produced PLT concentrates in the Netherlands from 2003 to 2014. RESULTS: Fourteen cases of TTBIs were reported, of which 57.1% received a PLT concentrate stored in PLT additive solution (PAS) and 42.9% a PLT concentrate stored in plasma. Of all produced PLT concentrates 22.3% were stored in PAS and 77.7% in plasma. The relative risk of TTBI after transfusion of a PAS-stored PLT concentrate was 4.63 (95% confidence interval [CI], 1.4-16.2) compared to transfusion of a plasma-stored PLT concentrate. The incidence of TTBIs was 22.2 per million (95% CI, 12.1-37.2 per million) transfused buffy coat PLT concentrates. CONCLUSION: Transfusion of PAS-stored PLT concentrates is associated with a fourfold increased incidence of TTBIs, compared to plasma-stored PLT concentrates.