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.

Risk factors for bleeding in haemato-oncology patients-a nested case-control study: The BITE study protocol (Bleeding In Thrombocytopenia Explained).

INTRODUCTION: Haemato-oncological patients often receive platelet count driven prophylactic platelet transfusions to prevent bleeding. However, many prophylactically transfused patients still bleed. More knowledge on risk factors for bleeding is therefore needed. This will enable identification of bleeding risk profiles on which future transfusion policy can be optimised. The present BITE study (Bleeding In Thrombocytopenia Explained) aims to identify clinical conditions and biomarkers that are associated with clinically relevant bleeding events. METHODS AND ANALYSIS: A matched case-control study nested in a cohort of haemato-oncological patients in the Netherlands. We collect a limited number of variables from all eligible patients, who together form the source population. These patients are followed for the occurrence of clinically relevant bleeding. Consenting patients of the source population form the cohort. Cases from the cohort are frequency matched to selected control patients for the nested case-control study. Of both case and control patients more detailed clinical data is collected. STUDY POPULATION: Adult haemato-oncological patients, who are admitted for intensive chemotherapeutic treatment or stem cell transplantation, or who received such treatments in the past and are readmitted for disease or treatment-related adverse events. STATISTICAL ANALYSIS: Bleeding incidences will be calculated for the total source population, as well as for different subgroups. The association between potential risk factors and the occurrence of bleeding will be analysed using conditional logistic regression, to account for matching of case and control patients. ETHICS AND DISSEMINATION: The study was approved by the Medical Research Ethics Committee Leiden Den Haag and Delft, and the Radboudumc Committee on Research Involving Human Subjects. Approval in seven other centres is foreseen. Patients will be asked for written informed consent and data is coded before analyses, according to Dutch privacy law. Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL62499.058.17. NCT03505086; Pre-results.

Fresh frozen plasma and platelet concentrate storage duration not associated with in hospital mortality risk.

BACKGROUND AND OBJECTIVES: To date, the effects of FFP and PC storage duration on mortality have only been studied in a few studies in limited patient subpopulations. The aim of the current study was to determine whether FFP and PC storage duration is associated with increased in hospital mortality risk across cardiac surgery, acute medicine, ICU and orthopaedic surgery patients. MATERIALS AND METHODS: Two-stage individual patient data meta-analyses were performed to determine the effects of FFP and PC storage duration on in hospital mortality. Preset random effects models were used to determine pooled unadjusted and adjusted (adjusted for age, gender and units of product transfused) effect estimates. RESULTS: The FFP storage duration analysis included 3625 patients across four studies. No significant association was observed between duration of storage and in hospital mortality in unadjusted analysis, but after adjusting for patient age, gender and units of product a small increased risk of in hospital mortality was observed for each additional month of storage (OR: 1·05, 95% CI: 1·01-1·08). This effect was no longer statistically significant when donor ABO blood group was incorporated into the random effects model on post hoc analyses. A total of 547 patients across five studies were incorporated in the PC storage duration analysis. No association was observed between PC storage duration and odds of in hospital morality (adjusted OR: 0·94, 95% CI: 0·79-1·11). CONCLUSIONS: There is insufficient evidence to support shortening FFP or PC shelf life based on in hospital mortality.

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.

Thrombocytopenia and bleeding in myelosuppressed transfusion-dependent patients: a simulation study exploring underlying mechanisms.

BACKGROUND: Hematology-oncology patients often become severely thrombocytopenic and receive prophylactic platelet transfusions when their platelet count drops below 10×109 platelets/L. This so-called "platelet count trigger" of 10×109 platelets/L is recommended because currently available evidence suggests this is the critical concentration at which bleeding risk starts to increase. Yet, exposure time and lag time may have biased the results of studies on the association between platelet counts and bleeding risks. METHODS: We performed simulation studies to examine possible effects of exposure time and lag time on the findings of both randomized trials and observational data. RESULTS: Exposure time and lag time reduced or even reversed the association between the risk of clinically relevant bleeding and platelet counts. The frequency of platelet count measurements influenced the observed bleeding risk at a given platelet count trigger. A transfusion trigger of 10×109 platelets/L resulted in a severely distorted association, which closely resembled the association reported in the literature. At triggers of 0, 5, 10, and 20×109 platelets/L the observed percentages of patients experiencing bleeding were 18, 19, 19, and 18%. A trigger of 30×109 platelets/L showed an observed bleeding risk of 16% and triggers of 40 and 50×109 platelets/L both resulted in observed bleeding risks of 13%. CONCLUSION: The results from our simulation study show how minimal exposure times and lag times may have influenced the results from previous studies on platelet counts, transfusion strategies, and bleeding risk and caution against the generally recommended universal trigger of 10×109 platelets/L.

Age of platelet concentrates and time to the next transfusion.

BACKGROUND: Storage time of platelet (PLT) concentrates has been negatively associated with clinical efficacy outcomes. The aim of this study was to quantify the association between storage time of PLT concentrates and interval to the next PLT transfusion for different types of PLT components, stored for up to 7 days and transfused to transfusion-dependent hematooncology patients with thrombocytopenia. STUDY DESIGN AND METHODS: From a cohort of patients from 10 major Dutch hospitals, patients were selected whose transfusion patterns were compatible with PLT transfusion dependency due to hematooncologic disease. Mean time to the next transfusion and mean differences in time to the next transfusion for different storage time categories (i.e., fresh, <4 days; intermediate, 4-5 days; and old, >5 days) were estimated, per component type, using multilevel mixed-effects linear models. RESULTS: Among a cohort of 29,761 patients who received 140,896 PLT transfusions we selected 4441 hematooncology patients who had received 12,724 PLT transfusions during periods of PLT transfusion dependency. Transfusion of fresh, compared to old, buffy coat-derived PLTs in plasma was associated with a delay to the next transfusion of 6.2 hours (95% confidence interval [CI], 4.5-8.0 hr). For buffy coat-derived PLTs in PAS-B and -C this difference was 7.7 hours (95% CI, 2.2-13.3 hr) and 3.9 hours (95% CI, -2.1 to 9.9 hr) while for apheresis PLTs in plasma it was only 1.8 hours (95% CI, -3.5 to 7.1 hr). CONCLUSION: Our results indicate that the time to the next transfusion shortens with increasing age of transfused buffy coat-derived PLT concentrates. This association was not observed for apheresis PLTs.

Impact of red blood cell transfusion strategies in haemato-oncological patients: a systematic review and meta-analysis.

Haemato-oncological patients receive many red blood cell (RBC) transfusions, however evidence-based guidelines are lacking. Our aim is to quantify the effect of restrictive and liberal RBC transfusion strategies on clinical outcomes and blood use in haemato-oncological patients. A literature search, last updated on 11 August 2016, was performed in PubMed, EMBASE (Excerpta Medica Database), Web of Science, Cochrane, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Academic Search Premier without restrictions on language and year of publication. Randomized controlled trials and observational studies that compared different RBC transfusion strategies in haemato-oncological patients were eligible for inclusion. Risk of bias assessment according to the Cochrane collaboration's tool and Newcastle-Ottawa scale was performed. After removing duplicates, 1142 publications were identified. Eventually, 15 studies were included, reporting on 2636 patients. The pooled relative risk for mortality was 0·68 [95% confidence interval (CI) 0·46-1·01] in favour of the restrictive strategy. The mean RBC use was reduced with 1·40 units (95% CI 0·70-2·09) per transfused patient per therapy cycle in the restrictive strategy group. There were no differences in safety outcomes. All currently available evidence suggests that restrictive strategies do not have a negative impact regarding clinical outcomes in haemato-oncological patients, while it reduces RBC use and associated costs.

Treatments for hematologic malignancies in contrast to those for solid cancers are associated with reduced red cell alloimmunization.

Red cell alloimmunization may induce severe hemolytic side effects. Identification of risk-modifying conditions will help tailor preventative strategies. This study aims to quantify the associations of hematologic malignancies and solid cancers with red cell alloimmunization in patients receiving red cell transfusions. We performed a nested multicenter case-control study in a source population of 24,063 patients receiving their first and subsequent red cell transfusions during an 8-year follow-up period. Cases (n=505), defined as patients developing a first transfusion-induced red cell alloantibody, were each compared with 2 non-alloimmunized controls (n=1010) who received a similar number of red cell units. Using multivariate logistic regression analyses, we evaluated the association of various malignancies and treatment regimens with alloimmunization during a delineated 5-week risk period. The incidence of alloimmunization among patients with acute (myeloid or lymphoid) leukemia and mature (B- or T-cell) lymphoma was significantly reduced compared to patients without these malignancies: adjusted relative risks (RR) with 95% confidence interval (CI) 0.36 (range 0.19-0.68) and 0.30 (range 0.12-0.81). Associations were primarily explained by immunosuppressive treatments [RR for (any type of) chemotherapy combined with immunotherapy 0.27 (95%CI: 0.09-0.83)]. Alloimmunization risks were similarly diminished in allogeneic or autologous stem cell transplanted patients (RR 0.34, 95%CI: 0.16-0.74), at least during the six months post transplant. Alloimmunization risks of patients with other hematologic diseases or solid cancers, and their associated treatment regimens were similar to risks in the general transfused population. Our findings suggest that, in contrast to malignancies in general, hemato-oncological patients treated with dose-intensive regimens have strongly diminished risk of red cell alloimmunization.

A study protocol for a randomised controlled trial evaluating clinical effects of platelet transfusion products: the Pathogen Reduction Evaluation and Predictive Analytical Rating Score (PREPAReS) trial.

INTRODUCTION: Patients with chemotherapy-induced thrombocytopaenia frequently experience minor and sometimes severe bleeding complications. Unrestrictive availability of safe and effective blood products is presumed by treating physicians as well as patients. Pathogen reduction technology potentially offers the opportunity to enhance safety by reducing bacterial and viral contamination of platelet products along with a potential reduction of alloimmunisation in patients receiving multiple platelet transfusions. METHODS AND ANALYSIS: To test efficacy, a randomised, single-blinded, multicentre controlled trial was designed to evaluate clinical non-inferiority of pathogen-reduced platelet concentrates treated by the Mirasol system, compared with standard plasma-stored platelet concentrates using the percentage of patients with WHO grade ≥ 2 bleeding complications as the primary endpoint. The upper limit of the 95% CI of the non-inferiority margin was chosen to be a ≤ 12.5% increase in this percentage. Bleeding symptoms are actively monitored on a daily basis. The adjudication of the bleeding grade is performed by 3 adjudicators, blinded to the platelet product randomisation as well as by an automated computer algorithm. Interim analyses evaluating bleeding complications as well as serious adverse events are performed after each batch of 60 patients. The study started in 2010 and patients will be enrolled up to a maximum of 618 patients, depending on the results of consecutive interim analyses. A flexible stopping rule was designed allowing stopping for non-inferiority or futility. Besides analysing effects of pathogen reduction on clinical efficacy, the Pathogen Reduction Evaluation and Predictive Analytical Rating Score (PREPAReS) is designed to answer several other pending questions and translational issues related to bleeding and alloimmunisation, formulated as secondary and tertiary endpoints. ETHICS AND DISSEMINATION: Ethics approval was obtained in all 3 participating countries. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NTR2106; Pre-results.

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study.

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

Flow cytometric assessment of agonist-induced P-selectin expression as a measure of platelet quality in stored platelet concentrates.

BACKGROUND: Platelet (PLT) function in PLT concentrates declines during storage and is further affected by pathogen reduction treatment. Flow cytometric assessment of agonist-induced P-selectin expression can be used to assess PLT function in patients with thrombocytopenia. The aim of this study was to evaluate how this functional test relates to established in vitro measures of PLT function. STUDY DESIGN AND METHODS: Six units of PLTs in plasma and 6 units of riboflavin and ultraviolet (Mirasol, TerumoBCT)-treated PLTs in plasma were sampled on Days 2, 6, 8, and 10 after donation. PLT concentration, Annexin 5A staining, ThromboLUX (LightIntegra) thrombelastography, and P-selectin expression, both in unstimulated PLTs and in response to concentration series of adenosine diphosphate, collagen-related peptide, and thrombin receptor-activating peptide (TRAP), were measured. RESULTS: For PLTs in plasma Annexin 5A expression increased by 0.60% (95% confidence interval [CI], 0.40%-0.80%) and P-selectin expression increased by 1.2% (95% CI, 0.80%-1.6%) per day. Responsiveness to TRAP simultaneously decreased by 1.3% (95% CI, 0.80%-1.8%) per day. After Mirasol treatment ThromboLUX scores decreased 3.3 points (95% CI, 0.2-6.4 points) from 22 to 19 points, Annexin 5A expression increased by 4.8% (95% CI, 3.3%-6.2%), and P-selectin expression increased by 13% (95% CI, 10%-16%), all averaged over the entire storage period. Responsiveness to TRAP simultaneously decreased by 19% (95% CI, 17%-21%). CONCLUSIONS: Our results suggest flow cytometric measurement of agonist-induced P-selectin expression can measure PLT quality decline over the entire range encountered during 10-day storage of both standard PLTs and Mirasol-treated PLTs in plasma.