Medical nutrition therapy during intensive remission-induction treatment and hematopoietic stem cell transplantation in acute myeloid leukemia patients: Hematologists' experiences and perspectives.

BACKGROUND & AIMS: The European Societies for Clinical Nutrition and Metabolism (ESPEN) and Blood and Marrow Transplantation (EBMT) recommend enteral nutrition (EN) as the first-choice medical nutrition therapy in acute myeloid leukemia (AML) patients undergoing intensive treatments, including high-dose remission-induction chemotherapy and hematopoietic stem cell transplantation (HSCT). However, parenteral nutrition (PN) remains the preferred method of nutrition support in current clinical practice. The aim of this qualitative study was to gain insight into hematologists' experiences and perspectives regarding the choice and ESPEN/EBMT recommendations on EN versus PN. METHODS: Online semi-structured interviews were conducted with one hematologist from each of the 21 hospitals offering intensive AML treatments in the Netherlands, using Microsoft Teams. Interviews were audio-recorded, transcribed verbatim and thematically analyzed using Atlas. ti. One hundred nineteen hematologists working in the same hospitals were invited to complete a short online questionnaire survey (SurveyMonkey®) regarding their knowledge and opinion on the ESPEN/EBMT guidelines recommending EN over PN during intensive AML treatments. The results of this survey are presented in a descriptive way. RESULTS: Fifty-nine hematologists participated in this study (42% overall response rate), of which 21 in the semi-structured interviews (response rate 100%) and 38 in the online survey (response rate 32%). Hematologists considered medical nutrition therapy important for prevention and treatment of malnutrition and associated adverse outcomes in AML patients undergoing intensive remission-induction treatment and HSCT. However, opposed to the ESPEN/EBMT guidelines, the vast majority of hematologists were hesitant or reluctant to use EN instead of PN as the first-choice medical nutrition therapy in these patients. The most frequently cited barriers to use EN were the expected low feasibility and tolerance of EN, feeding tube-related discomfort and bleeding risk, and patient refusal. Other barriers to follow the guidelines on EN were related to personal factors, including hematologists' knowledge (lack of awareness and familiarity) and attitude (lack of agreement, outcome expectancy, experience, success, motivation, and learning culture), guideline-related factors (lack of evidence and applicability), and external factors (lack of collaboration and resources). Facilitators included strategies for nutrition education and dissemination of nutritional guidelines, interprofessional and patient collaboration, availability of feeding tubes that can be inserted without endoscopy and stronger scientific evidence. CONCLUSIONS: Hematologists recognized the importance of medical nutrition therapy for reducing malnutrition and related negative outcomes during intensive AML treatments. However, contrary to the ESPEN/EBMT guidelines, they preferred PN instead of EN as the medical nutrition therapy of first choice. To reduce compliance barriers, interventions should focus on improving hematologists' knowledge of medical nutrition therapy and dietary guidelines, enhancing success rates of EN by adequately triaging patients eligible for EN and inserting duodenal feeding tubes using an electromagnetic sensing device without endoscopy, developing decision aids and multidisciplinary guidelines and care pathways. Furthermore, future trials should focus on the feasibility and benefits of EN versus PN both during remission-induction treatment and HSCT.

Serial thrombin generation and exploration of alternative anticoagulants in critically ill COVID-19 patients: Observations from Maastricht Intensive Care COVID Cohort.

Background: COVID-19 associated coagulopathy (CAC) is associated with an increase in thromboembolic events. Current guidelines recommend prophylactic heparins in the management of CAC. However, the efficacy of this strategy in the intensive care population remains uncertain. Objective: We aimed to measure thrombin generation (TG) to assess CAC in intensive care unit (ICU) patients receiving thromboprophylaxis with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). In addition, we performed statistical modeling to link TG parameters to patient characteristics and clinical parameters. Lastly, we studied the potency of different anticoagulants as an alternative to LMWH treatment in ex vivo COVID-19 plasma. Patients/Methods: We included 33 patients with confirmed COVID-19 admitted at the ICU. TG was measured at least twice over the course of 6 weeks after admission. Thrombin generation parameters peak height and endogenous thrombin potential (ETP) were compared to healthy controls. Results were subsequently correlated with a patient characteristics and laboratory measurements. In vitro spiking in TG with rivaroxaban, dabigatran, argatroban and orgaran was performed and compared to LMWH. Results: Anti-Xa levels of all patients remained within the therapeutic range throughout follow-up. At baseline, the mean (SE) endogenous thrombin potential (ETP) was 1,727 (170) nM min and 1,620 (460) nM min for ellagic acid (EA) and tissue factor (TF), respectively. In line with this we found a mean (SE) peak height of 353 (45) nM and 264 (96) nM for EA and TF. Although fluctuating across the weeks of follow-up, TG parameters remained elevated despite thromboprophylaxis. In vitro comparison of LMWHs and direct thrombin inhibitors (e.g., agratroban, dabigatran) revealed a higher efficacy in reducing coagulation potential for direct thrombin inhibition in both ellagic acid (EA) and tissue factor (TF) triggered TG. Conclusion: In a sub-group of mechanically ventilated, critically ill COVID-19 patients, despite apparent adequate anti-coagulation doses evaluated by anti-Xa levels, thrombin generation potential remained high during ICU admission independent of age, sex, body mass index, APACHE II score, cardiovascular disease, and smoking status. These observations could, only partially, be explained by (anti)coagulation and thrombosis, inflammation, and multi-organ failure. Our in vitro data suggested that direct thrombin inhibition compared with LMWH might offer an alternate, more effective anticoagulant strategy in COVID-19.

Nutrition-related problems, nutritional support practices and barriers to adherence to nutritional guidelines during intensive treatment for acute myeloid leukemia: Patients' and hematology nurses' perspectives and experiences.

BACKGROUND & AIMS: The updated guidelines of the European Society for Clinical Nutrition and Metabolism (ESPEN) and for Blood and Marrow Transplantation (EBMT) on nutrition in intensively treated acute myeloid leukemia (AML) patients recommend enteral nutrition (EN) instead of parenteral nutrition (PN) as the first-choice medical nutrition therapy. Despite this, PN remains the preferred route of nutrition administration in daily practice. The aim of this qualitative study was to gain insight into the patients' and hematology nurses' experiences and perceptions regarding nutritional problems and nutritional support and the reasons for the low adherence to the ESPEN/EBMT guidelines. METHODS: Semi-structured interviews were conducted in 23 patients from various Dutch hospitals who had completed intensive AML treatment. Interviews with 22 patients were audio-recorded and transcribed, one interview was summarized. The transcripts and summary were thematically analyzed using Atlas.ti. From each of the 22 Dutch hospitals providing intensive AML treatment, one hematology nurse participated in a telephone questionnaire survey. The results of this survey are presented in a descriptive way. RESULTS: Nutritional problems were a major source of distress in most participating patients. Nutritional support often led to peace of mind and less concerns, provided that there were no conflicting nutritional support practices among treating hospitals. Patients perceived PN and EN as a life-line and necessary for the prevention of or recovery from physical decline, but they also experienced loss of independence, limited mobility, fear of unwanted body weight gain and problems related to the feeding equipment. Both patients and hematology nurses regarded PN as an easy method of nutrition administration, while EN was often seen as a necessary evil or was even refused by patients, owing to tube-related physical discomfort and EN intolerance. Both patients' and hematology nurses' reluctance to administer EN proved to be barriers to the ESPEN/EBMT nutritional guideline adherence. Among the surveyed hematology nurses, barriers to adherence included personal factors related to their knowledge (lack of awareness) and attitudes (negative outcome expectancy and lack of agreement), guideline-related factors (lack of evidence) and external factors (lack of collaboration). CONCLUSION: Individualized nutritional support, including EN and PN, may reduce nutrition-related distress in intensively treated AML patients, provided that conflicting nutritional support practices among hospitals are avoided or explained. The barriers to adherence to the ESPEN/EBMT guidelines on EN and PN in this patient group may be reduced by enhancing hematology nurses' awareness and knowledge of the guidelines, incorporating the guidelines into multidisciplinary clinical pathways, improving outcome of EN by proper triage of patients eligible for EN and increasing the level of evidence of the guidelines.

Assessment of need for hemostatic evaluation in patients taking valproic acid: A retrospective cross-sectional study.

INTRODUCTION: Valproic acid (VPA) is a frequently prescribed anti-epileptic drug. Since its introduction side effects on hemostasis are reported. However, studies show conflicting results, and the clinical relevance is questioned. We aimed to determine the coagulopathies induced by VPA in patients who undergo high-risk surgery. The study results warrant attention to this issue, which might contribute to reducing bleeding complications in future patients. METHODS: Between January 2012 and August 2020, 73 consecutive patients using VPA were retrospectively included. Extensive laboratory hemostatic assessment (including platelet function tests) was performed before elective high-risk surgery. Patient characteristics, details of VPA treatment, and laboratory results were extracted from medical records. RESULTS: 46.6% of the patients using VPA (n = 73) showed coagulopathy. Mainly, platelet function disorder was found (36.4%). Thrombocytopenia was seen in 9.6% of the patients. Data suggested that the incidence of coagulopathies was almost twice as high in children as compared to adults and hypofibrinogenemia was only demonstrated in children. No association was found between the incidence of coagulopathies and VPA dosage (mg/kg/day). CONCLUSION: A considerable number of patients using VPA were diagnosed with coagulopathy, especially platelet function disorder. Further prospective studies are needed to confirm the need for comprehensive laboratory testing before elective high-risk surgery in these patients.

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.

Perioperative pharmacokinetic-guided factor VIII concentrate dosing in haemophilia (OPTI-CLOT trial): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels. METHODS: In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of <0·01 IU/mL, and moderate haemophilia as 0·01-0·05 IU/mL), without factor VIII inhibitors, and planned for elective low or medium risk surgery as defined by surgical risk score. Patients were randomly assigned (1:1) using a web-based randomisation system and treatment minimisation, stratified by method of administration of factor VIII concentrate (continuous infusion vs bolus administration) and risk level of surgery (low and medium risk surgery), to the pharmacokinetic-guided or standard treatment group. The primary endpoint was total amount of infused factor VIII concentrate (IU per kg bodyweight) during perioperative period (from day of surgery up to 14 days after surgery). Analysis was by intention to treat and the safety analysis population comprised all participants who underwent surgery with factor VIII concentrate. This study is registered with the Netherlands Trial Registry, NL3955, and is now closed to accrual. FINDINGS: Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49·1 years (IQR 35·0 to 62·1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred. INTERPRETATION: Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care. FUNDING: Dutch Research Council (NWO)-ZonMw and Takeda.

Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018.

BACKGROUND: Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands. OBJECTIVE: This observational cohort study aimed to assess all-cause and cause-specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward. PATIENTS/METHODS: All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018. RESULTS: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2-1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time. CONCLUSIONS: Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.

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.

Treatment of acquired hemophilia A, a balancing act: results from a 27-year Dutch cohort study.

Acquired hemophilia A (AHA) is a severe auto-immune bleeding disorder. Treatment of AHA is burdensome and optimal management is still unresolved. Therefore a retrospective nationwide multi-center cohort study (1992-2018) was performed to evaluate clinical presentation and treatment efficacy and safety of AHA in the Netherlands. Multivariate logistic and Cox regression analysis was used to study independent associations between patient characteristics and clinical outcomes. A total of 143 patients (median age 73 years; 52.4% male) were included with a median follow-up of 16.8 months (IQR 3.6-41.5 months). First-line immunosuppressive treatment was mostly steroid monotherapy (67.6%), steroids/cyclophosphamide (11.9%) and steroids/rituximab (11.9%), with success rates of 35.2%, 80.0% and 66.7% respectively, P < .05. Eventually 75% of patients achieved complete remission (CR). A high anti-FVIII antibody titer, severe bleeding and steroid monotherapy were associated with lower CR rates. Infections, the most important adverse event, occurred significantly more often with steroid combination therapy compared to steroids alone (38.7% vs 10.6%; P = .001). Overall mortality was 38.2%, mostly due to infections (19.2%) compared to 7.7% fatal bleeds. Advanced age, underlying malignancy and ICU admission were predictors for mortality. This study showed that AHA is characterized by significant disease-related and treatment-related morbidity and mortality. A high anti-FVIII titer, severe bleeding and steroid monotherapy were associated with a lower CR rate. The efficacy of steroid combination therapies however, was overshadowed by higher infection rates and infections represented the most important cause of death. The challenging and delicate balance between treatment effectivity and safety requires ongoing monitoring of AHA and further identification of prognostic markers.

Anticoagulation in thrombocytopenic patients with hematological malignancy: A multinational clinical vignette-based experiment.

BACKGROUND: Thrombocytopenia in cancer patients with an indication for anticoagulation poses a unique clinical challenge. There are guidelines for the setting of venous thromboembolism but not atrial fibrillation (AF). Evidence is lacking and current practice is unclear. OBJECTIVE: To identify patient and physician characteristics associated with anticoagulation management in hematological malignancy and thrombocytopenia. METHODS: A clinical vignette-based experiment was designed. Eleven hematologists were interviewed, identifying 5 relevant variable categories with 2-5 options each. Thirty hypothetical vignettes were generated. Each physician received 5 vignettes and selected a management strategy (hold anticoagulation; no change; transfuse platelets; modify type/dose). The survey was distributed to hematologists and thrombosis specialists in 3 countries. Poisson regression models with cluster robust variance estimates were used to calculate relative risks for using one management option over the other, for each variable in comparison to a reference variable. RESULTS: 168 physicians answered 774 cases and reported continuing anticoagulation for venous thromboembolism or AF in 607 (78%) cases, usually with dose reduction or platelet transfusion support. Overall, management was affected by platelet count, anticoagulation indication, time since indication, type of hematological disease and treatment, and prior major bleeding, as well as physician demographics and practice setting. The CHA2DS2-VASc score and time since AF diagnosis affected anticoagulation management in AF. CONCLUSION: This study indicates what the widely accepted management strategies are. These strategies, and possibly others, should be assessed prospectively to ascertain effectiveness. The decision process is intricate and compatible with current venous thromboembolism guidelines.

Desmopressin treatment combined with clotting factor VIII concentrates in patients with non-severe haemophilia A: protocol for a multicentre single-armed trial, the DAVID study.

INTRODUCTION: Haemophilia A is an inherited bleeding disorder characterised by factor VIII (FVIII) deficiency. In patients with non-severe haemophilia A, surgery and bleeding are the main indications for treatment with FVIII concentrate. A recent study reported that standard dosing frequently results in FVIII levels (FVIII:C) below or above FVIII target ranges, leading to respectively a bleeding risk or excessive costs. In addition, FVIII concentrate treatment carries a risk of development of neutralising antibodies. An alternative is desmopressin, which releases endogenous FVIII and von Willebrand factor. In most patients with non-severe haemophilia A, desmopressin alone is not enough to achieve FVIII target levels during surgery or bleeding. We hypothesise that combined pharmacokinetic (PK)-guided administration of desmopressin and FVIII concentrate may improve dosing accuracy and reduces FVIII concentrate consumption. METHODS AND ANALYSIS: In the DAVID study, 50 patients with non-severe haemophilia A (FVIII:C ≥0.01 IU/mL) with a bleeding episode or undergoing surgery will receive desmopressin and FVIII concentrate combination treatment. The necessary dose of FVIII concentrate to reach FVIII target levels after desmopressin administration will be calculated with a population PK model. The primary endpoint is the proportion of patients reaching FVIII target levels during the first 72 hours after start of the combination treatment. This approach was successfully tested in one pilot patient who received perioperative combination treatment. ETHICS AND DISSEMINATION: The DAVID study was approved by the medical ethics committee of the Erasmus MC. Results of the study will be communicated trough publication in international scientific journals and presentation at (inter)national conferences. TRIAL REGISTRATION NUMBER: NTR5383; Pre-results.

Fibrinolysis in patients with chemotherapy-induced thrombocytopenia and the effect of platelet transfusion.

Essentials Bleeding in chemotherapy induced thrombocytopenia (CIT) might be influenced by hyperfibrinolysis. t-PA-thromboelastography is a fast and reliable assay for hyperfibrinolysis in CIT patients. Clots of CIT patients are more susceptible to t-PA induced lysis compared to healthy individuals. Besides platelets, other factors are likely to influence clot lysis in CIT patients. BACKGROUND: Bleeding events in chemotherapy-induced thrombocytopenic (CIT) patients with similar platelet counts might be influenced by changes in clot lysis potential. OBJECTIVES: To investigate, in an observational study, thromboelastographic lysis parameters, alterations in clot strength and susceptibility to clot lysis in CIT patients. To identify factors associated with fibrinolytic profiles, and to evaluate the effects of platelet transfusions. METHODS: Independent determinants of tissue-type plasminogen activator (t-PA)-ROTEM lysis parameters were identified with multivariable linear regression. Clot formation, strength and lysis parameters were compared with the results of healthy individuals. Characteristics of CIT patients with and without hyperfibrinolytic profiles were compared. t-PA-ROTEM results before, 1 hour after and 24 hours after platelet transfusion were compared. RESULTS: A total of 72 consecutive CIT patients were included. t-PA-ROTEM lysis parameters correlated with changes in fibrinolytic proteins. Clot formation time was longer, maximum clot firmness was weaker and lysis times were shorter than in healthy individuals. CIT patients had low plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor levels, and 40% showed hyperfibrinolytic profiles. Platelet transfusions resulted in less hyperfibrinolytic profiles in many, but not all CIT patients. Patients without hyperfibrinolytic profiles had higher fibrinogen, factor VIII and α2 -antiplasmin levels. CONCLUSIONS: t-PA-ROTEM can be used as a fast and reliable assay to detect hyperfibrinolytic profiles in CIT patients. CIT patients have weaker clots, which are more susceptible to clot lysis, than healthy individuals. Besides platelets, other factors are likely to influence clot susceptibility to fibrinolysis in CIT patients. The impact of a hyperfibrinolytic t-PA-ROTEM profile on bleeding remains to be investigated.

Managing Anti-Platelet Therapy in Thrombocytopaenic Patients with Haematological Malignancy: A Multinational Clinical Vignette-Based Experiment.

Data on anti-platelet therapy (APT) for prevention of atherothrombotic events in thrombocytopaenic cancer patients is lacking. We aimed to identify patient and physician characteristics associated with APT management in thrombocytopaenic patients with haematological malignancy. A clinical vignette-based experiment was designed. Eleven haematologists were interviewed, identifying five variable categories. Next, 18 hypothetical vignettes were generated. Each physician received three vignettes and chose to: hold all APT; continue APT without platelet transfusion support; or continue APT with platelet transfusion support. The survey was distributed to haematologists and thrombosis specialists in three countries. Multivariate cluster robust Poisson regression models were used to calculate relative risks (RRs) of using one management option (over the other) for each variable in comparison to a reference variable. A total of 145 physicians answered 434 cases. Clinicians were more likely to hold APT in case of 20,000/µL platelets (vs. 40,000/µL; RR for continuing: 0.82 [95% confidence interval: 0.75-0.91]), recent major gastrointestinal bleeding (vs. none; RR 0.81 [0.72-0.92]) and when the physician worked at a university-affiliated community hospital (vs. non-academic community hospital; RR 0.84 [0.72-0.98]). Clinicians were more likely to continue APT in ST elevation myocardial infarction with dual APT (vs. unstable angina with single APT; RR 1.31 [1.18-1.45]) and when there were institutional protocols guiding management (vs. none; RR 1.15 [1.03-1.27]). When APT was continued, increased platelet transfusion targets were used in 34%. In summary, the decision process is complex and affected by multiple patient and physician characteristics. Platelet transfusions were frequently chosen to support APT, although no evidence supports this practice.

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.

Impaired mitochondrial activity explains platelet dysfunction in thrombocytopenic cancer patients undergoing chemotherapy.

Severe thrombocytopenia (≤50×109 platelets/L) due to hematological malignancy and intensive chemotherapy is associated with an increased risk of clinically significant bleeding. Since the bleeding risk is not linked to the platelet count only, other hemostatic factors must be involved. We studied platelet function in 77 patients with acute leukemia, multiple myeloma or malignant lymphoma, who experienced chemotherapy-induced thrombocytopenia. Platelets from all patients - independent of disease or treatment type - were to a variable extent compromised in Ca2+ flux, integrin a ß activation and P-selectin expression when stimulated with a panelIIbof3 agonists. The patients' platelets were also impaired in spreading on fibrinogen. Whereas the Ca2+ store content was unaffected, the patients' platelets showed ongoing phosphatidylserine exposure, which was not due to apoptotic caspase activity. Interestingly, mitochondrial function was markedly reduced in platelets from a representative subset of patients, as evidenced by a low mitochondrial membrane potential (P<0.001) and low oxygen consumption (P<0.05), while the mitochondrial content was normal. Moreover, the mitochondrial impairments coincided with elevated levels of reactive oxygen species (Spearman's rho=-0.459, P=0.012). Markedly, the impairment of platelet function only appeared after two days of chemotherapy, suggesting origination in the megakaryocytes. In patients with bone marrow recovery, platelet function improved. In conclusion, our findings disclose defective receptor signaling related to impaired mitochondrial bioenergetics, independent of apoptosis, in platelets from cancer patients treated with chemotherapy, explaining the low hemostatic potential of these patients.

Hemostatic efficacy of pathogen-inactivated vs untreated platelets: a randomized controlled trial.

Pathogen inactivation of platelet concentrates reduces the risk for blood-borne infections. However, its effect on platelet function and hemostatic efficacy of transfusion is unclear. We conducted a randomized noninferiority trial comparing the efficacy of pathogen-inactivated platelets using riboflavin and UV B illumination technology (intervention) compared with standard plasma-stored platelets (control) for the prevention of bleeding in patients with hematologic malignancies and thrombocytopenia. The primary outcome parameter was the proportion of transfusion-treatment periods in which the patient had grade 2 or higher bleeding, as defined by World Health Organization criteria. Between November 2010 and April 2016, 469 unique patients were randomized to 567 transfusion-treatment periods (283 in the control arm, 284 in the intervention arm). There was a 3% absolute difference in grade 2 or higher bleeding in the intention-to-treat analysis: 51% of the transfusion-treatment periods in the control arm and 54% in the intervention arm (95% confidence interval [CI], -6 to 11; P = .012 for noninferiority). However, in the per-protocol analysis, the difference in grade 2 or higher bleeding was 8%: 44% in the control arm and 52% in the intervention arm (95% CI -2 to 18; P = .19 for noninferiority). Transfusion increment parameters were ∼50% lower in the intervention arm. There was no difference in the proportion of patients developing HLA class I alloantibodies. In conclusion, the noninferiority criterion for pathogen-inactivated platelets was met in the intention-to-treat analysis. This finding was not demonstrated in the per-protocol analysis. This trial was registered at The Netherlands National Trial Registry as #NTR2106 and at www.clinicaltrials.gov as #NCT02783313.

Evaluation of Dutch guideline for just-in-time addition of plerixafor to stem cell mobilization in patients who fail with granulocyte-colony-stimulating factor.

BACKGROUND: Plerixafor in combination with granulocyte-colony-stimulating factor (G-CSF) is approved for the use of stem cell collection in patients who fail to mobilize on G-CSF. In 2009 the Stem Cell Working Party of the Dutch-Belgian Cooperative Trial group for Hematology Oncology (HOVON) composed a guideline for the use of plerixafor. According to this guideline it is recommended to add plerixafor to G-CSF in patients with circulating CD34+ cell counts of fewer than 20 × 10(6) /L on 2 consecutive days accompanied by increasing white blood cells. STUDY DESIGN AND METHODS: In this analysis we evaluated retrospectively the outcome of the use of this guideline in the Netherlands. In total 111 patients received plerixafor with a median one administration (range, one to four administrations). Of these patients 55.8% had non-Hodgkin lymphoma, 31.5% multiple myeloma, 8.1% Hodgkin lymphoma, and 4.5% nonhematologic malignancies. RESULTS: In 63.9% patients sufficient numbers of CD34+ cells were collected. In patients with multiple myeloma more successful mobilizations with plerixafor were observed compared to patients with non-Hodgkin lymphoma (71.4% vs. 61.3%). In patients with circulating CD34+ cell counts of at least 2.0 × 10(6) /L before administration of plerixafor a successful mobilization was achieved in 76.5%, and in the patients with very low (0-1 × 10(6) /L) circulating CD34+ cell counts the success rate was 44.2%. CONCLUSION: Application of the HOVON guideline on the just-in-time administration of plerixafor is effective for mobilization of hematopoietic stem cells in the majority of patients. Stem cell yield in patients with non-Hodgkin lymphoma was lower compared to patients with multiple myeloma. Also patients with very low circulating CD34+ cells before addition of plerixafor might benefit from this approach.

Immature platelet fraction measured on the Sysmex XN hemocytometer predicts thrombopoietic recovery after autologous stem cell transplantation.

OBJECTIVES: A period of thrombocytopenia is common after stem cell transplantation (SCT). To prevent serious bleeding complications, prophylactic platelet transfusions are administered. Previous studies have shown that a rise in immature platelets precedes recovery of platelet count. Our aim was to define a cutoff value for immature platelets predicting thrombopoietic recovery within 2 d. METHODS: Hematological parameters were measured on the Sysmex XN hemocytometer. We calculated reference change values (RCV) for platelets in eight healthy individuals as marker for platelet recovery. To define a cutoff value, we performed ROC analysis using data from 16 autologous SCT patients. RESULTS: RCV for platelet concentration was 14.1%. Platelet recovery was observed 13 (median; range 9-31) days after SCT. Increase in immature platelet fraction (IPF) before platelet recovery was seen in all autologous SCT patients. Optimal cutoff IPF was found to be 5.3% for platelet recovery within 2 d (specificity 0.98, sensitivity 0.47, positive predictive value 0.93). CONCLUSIONS: We identified an optimal cutoff value for IPF 5.3% to predict platelet recovery after autologous SCT within 2 d. Implementing this cutoff value in transfusion strategy may reduce the number of prophylactic platelet transfusions.

Rapid and correct prediction of thrombocytopenia and hypofibrinogenemia with rotational thromboelastometry in cardiac surgery.

OBJECTIVES: In the present study, the authors have investigated whether rotational thromboelastometry (ROTEM) could predict thrombocytopenia and hypofibrinogenemia in cardiac surgery using the clot amplitude after 5 minutes (A5). Another parameter, PLTEM, in which the contribution of fibrinogen is eliminated by subtracting a fibrin-specific ROTEM test (FIBTEM) from an extrinsically-activated ROTEM test (EXTEM), was investigated. Furthermore, the turnaround time of ROTEM was compared to conventional laboratory tests. DESIGN: Prospective cohort study. SETTING: Single academic medical center. PARTICIPANTS: Ninety-seven patients undergoing cardiac surgery between July 2011 until August 2012. INTERVENTIONS: The correlations between EXTEM/FIBTEM A5, A10, and maximal clot formation (MCF), EXTEM/PLTEM (A5/A10, and MCF) and platelet count, and FIBTEM (A5/A10, and MCF) and fibrinogen were evaluated using the Pearson's correlation coefficient and receiver-operating characteristic curves. Turnaround times of ROTEM tests and conventional laboratory tests were assessed in the central laboratory. MEASUREMENTS AND MAIN RESULTS: EXTEM A5 and FIBTEM A5 showed an excellent correlation with A10 (R:0.99/1.00) and MCF (R:0.97/0.99). The correlation between EXTEM A5 and platelet count (R:0.74) was comparable with the correlation of A10 (R:0.73) and MCF (R:0.70) with platelet count. FIBTEM A5 predicted fibrinogen levels (R:0.87) as well as A10 (R:0.86) and MCF (R:0.87). PLTEM A5 (R:0.85) correlated better with platelet count than EXTEM A5 (R:0.74; p = 0.04) and showed significantly better area under the curve values than EXTEM for predicting thrombocytopenia (A5 p = 0.012, A10 p = 0.019). Turnaround time for ROTEM tests, 12 minutes, was comparable with emergency requests for platelet count, 13 minutes, and shorter than emergency requests for fibrinogen levels, 37 minutes. CONCLUSIONS: Implementation of PLTEM and FIBTEM A5 in ROTEM-guided transfusion protocols may improve transfusion management.