Biomarkers of bone disease in persons with haemophilia.

INTRODUCTION: Persons with haemophilia (PwH) have abnormally low bone density and increased risk of fractures. We previously demonstrated decreased skeletal health in factor VIII (FVIII)-deficient mice. Thus, we hypothesized factor deficiency is an independent risk factor for decreased skeletal health. AIM: We seek to identify differences in bone-related cytokine expression among PwH and healthy controls. METHODS: We evaluated plasma samples from 79 participants with severe FVIII deficiency and 51 age-matched healthy controls. Plasma samples were assessed for RANKL and OPG, cytokines that regulate bone metabolism, and CTX-1, a biomarker for bone resorption, as well as 10 bone-related cytokines. RESULTS: CTX-1 is higher among samples from FVIII-deficient participants compared to controls (P < .01) but not among participants with recent factor use (within 24 hours of sample collection) (P = .21). Among PwH greater than 16 years of age (PwH ≥ 16), OPG is increased with recent factor use (P < .01) but not without (P = .34). Lower levels of TNF-α (P < .01), interleukin (IL)-12 (P < .01) and IL-10 (P < .001) were found among samples from PwH. Controlling for subject age, IL-12 and IL-10 levels are lower in PwH ≥ 16 (P < .01, P < .001) but not PwH under 16 (PwH < 16) (P > .05). Levels of TNF-α were lower among PwH < 16 only (P < .05). These differences are not observed in participants with recent factor use. CONCLUSIONS: In PwH, markers of bone metabolism and circulating cytokine levels are abnormal. Recent factor use reverses many of these differences suggesting FVIII replacement ameliorates this pathology. This study suggests bone disease present in PwH is intrinsic to FVIII deficiency.

Heavy menstrual bleeding in women on oral anticoagulants.

BACKGROUND: Although heavy menstrual bleeding (HMB) is a known complication of anticoagulant therapy, rates of HMB in users of the direct oral anticoagulants (OACs) apixaban and rivaroxaban are largely unknown. METHODS: We performed a retrospective cohort study of menstruating women prescribed rivaroxaban, apixaban and warfarin over a six-year period (2012-2018). The primary outcome was HMB requiring medical or surgical intervention. We used descriptive statistics and logistic regression to evaluate associations between OAC type, age, history of HMB, and the primary outcome. RESULTS: We identified 195 women of reproductive-age with a new therapeutic OAC prescription (62 on rivaroxaban, 54 on apixaban, 79 on warfarin). A minority (26/195, 13.3%) had a documented history of HMB, including 9 rivaroxaban users, 7 apixaban users and 10 warfarin users but most women (117/195, 60%) had no menstrual history documented. One third of subjects (64/195) required treatment for HMB within 6 months of starting OAC therapy. After controlling for a history of HMB, rivaroxaban users were 1.4 times more likely to require treatment as compared to users of other OACs. DISCUSSION: We found an association between rates of HMB necessitating medical or surgical intervention and rivaroxaban use. We also found that the majority of women did not have a documented menstrual history, suggesting that many providers do not inquire about menstrual bleeding when starting OAC therapy. Menstruating women, particularly those with a history of HMB, may be at increased risk for HMB necessitating medical treatment depending on the type of OAC used.

Delirium in the pediatric hematology, oncology, and bone marrow transplant population.

BACKGROUND: Delirium affects 10% to 30% of patients in pediatric intensive care units (PICU) and is associated with increased length of stay and prolonged late sequela. There are no prospective trials evaluating delirium in the pediatric hematology, oncology, and bone marrow transplant (PHO) population. Hypothesizing that delirium is underrecognized in this population, our study aimed to identify the prevalence of delirium in hospitalized PHO patients and associated risk factors. PROCEDURE: PHO and PICU nurses were trained to use the Cornell Assessment for Pediatric Delirium and to record scores once every 12-hour shift. Predetermined demographic and clinical variables were collected daily on all hospitalized PHO patients during the year-long prospective study. RESULTS: Prior to initiating routine delirium screening, 1.1% of PHO admissions and 2.4% of unique patients had delirium mentioned in a progress note. This study included 807 consecutive admissions: 671 oncology, 49 hematology, and 87 bone marrow transplant (BMT) hospitalizations among 223 unique PHO patients. The prevalence of delirium among hospitalizations was 5% and among unique patients was 13%. Among BMT hospitalizations, the prevalence was 23%. Multiple logistic regression identified significant association of delirium with increased length of stay, admission to the BMT service, patient location (PICU vs PHO unit), benzodiazepine, opioid, and anticholinergic administration. CONCLUSIONS: Before routine screening, delirium was underrecognized in this PHO-hospitalized population. Patients at highest risk had prolonged hospital stays, PICU admissions, BMT, and/or frequent use of benzodiazepines, opioids, or anticholinergics. Routine screening is feasible and may improve our recognition of delirium.

Preoperative platelet dysfunction predicts blood product transfusion in children undergoing cardiac surgery.

OBJECTIVES: Excessive bleeding can be a problem during or after cardiac surgery. While cardiopulmonary bypass-associated platelet dysfunction is an important inducer of coagulopathy, preoperative platelet dysfunction can also contribute to this bleeding. We investigated the relationship between preoperative platelet dysfunction and transfusion of blood products given to children undergoing cardiac surgery. METHODS: The platelet function analyser test measures platelet function in vitro by aspirating blood through a small standard hole (creating high shear) in a collagen membrane infused with a platelet agonist. The time taken to form a platelet plug is known as closure time and prolonged closure time (CT) indicates platelet dysfunction. Three hundred and thirty-eight children who had undergone surgery with cardiopulmonary bypass between 2008 and 2012 were included. The volume of red blood cells and fresh-frozen plasma transfused was recorded. The relationship between closure time and transfusion requirements was analysed using linear and logistic regression. RESULTS: Patients with prolonged closure time had greater odds of getting red blood cells and fresh-frozen plasma transfusions compared with patients with normal closure time (P <0.01). On univariate analysis, age, weight, haematocrit, cardiopulmonary bypass time, Risk Adjustment for Congenital Heart Surgery score and closure time were associated with increased odds of red blood cells and fresh-frozen plasma transfusion in the operation theatre (P <0.05). However, when logistic multivariable regression analysis was applied, only age, cardiopulmonary bypass time and closure time remained as significant predictive factors for transfusion. CONCLUSIONS: In children who have undergone cardiac surgery, when age and cardiopulmonary bypass time are accounted for, a prolonged preoperative closure time is significantly associated with increased odds of red blood cells and fresh-frozen plasma transfusion in the operation theatre. This may have implications for planning and utilization of blood products.

Congenital cardiac lesions involving systolic flow abnormalities are associated with platelet dysfunction in children.

BACKGROUND: Shear stress-induced platelet dysfunction (PD) is prevalent among adults with aortic stenosis. Our aim was to determine whether abnormal platelet function was associated with specific congenital cardiac lesions in children. METHODS: The charts of 407 children who had undergone cardiopulmonary bypass and had preoperative platelet function analysis were evaluated. Patients were assigned to 1 of 11 different lesion categories. Platelet dysfunction (PD) was defined as prolonged closure time (CT) as measured with a platelet function analyzer. Odds ratio (OR) estimates for prolonged CT were calculated for each lesion category. Mean CTs were compared with Tukey-Kramer separated means testing. Analysis of variance modeling was used to determine association between hematocrit value and CT. RESULTS: CT in patients with ventricular septal defects (VSD) and right ventricular outflow tract obstruction (RVOTO) lesions was prolonged. OR analysis found that patients with VSDs (OR, 2.46) or RVOTO (OR, 2.88) had at least a 95% probability of an abnormal CT. In contrast, patients with atrial septal defect (ASD), bidirectional Glenn procedure (BDG), and pulmonary insufficiency (PI) had a reduced probability of a prolonged CT (p < 0.05). A similar pattern was seen in parametric analysis comparing mean CTs across lesion categories. A lower preoperative hematocrit value was associated with prolonged CTs across all lesion types (p < 0.05). CONCLUSIONS: PD was common in children with congenital cardiac lesions involving systolic flow abnormalities and was uncommon among children with lesions having diastolic abnormalities. Lower preoperative hematocrit values were associated with prolonged CTs, suggesting subclinical bleeding secondary to excessive platelet shearing.