PLADO and kids: earlier/increased bleeding after HSCT

Patients, both pediatric and adult, who receive hematopoietic stem cell transplants (HSCTs) and/or chemotherapy for leukemia or other malignancies experience hypoproliferative thrombocytopenia rendering them at risk for bleeding. Although there is evidence that prophylactic platelet transfusions reduce the incidence of bleeding in these patients, there is a paucity of available information with regard to adequate platelet dosing per transfusion as well as a general lack of data that could be compared with current treatment and supportive care regimens. To this end, a secondary analysis of the PLADO clinical trial was conducted to determine whether bleeding outcomes differed among 4 distinct age groups: 3 pediatric (0-5 years, 6-12 years, and 13-18 years) and adults (> 18 years). Hospitalized patients were randomized to 1 of 3 platelet doses: 1.1 × 10¹¹, 2.2 × 10¹¹, or 4.4 × 10¹¹ platelet/m²/transfusion, administered for morning platelet counts of < 10 000/μL, and daily hemostatic assessments were performed. The primary end point was the percentage of patients who developed grade 2 or higher bleeding based on the World Health Organization scale, and a total of 198 children (0-18 years) and 1044 adults were evaluated. Platelet dose was not predictive for bleeding in any age group; however, children in all age groups had a significantly higher risk of grade 2 or higher bleeding (grade 3 but not 4) versus adults, earlier bleeding after HSCT, and more days of grade 2 bleeding than adults. Moreover, the effect of age on grade 2 bleeding differed by disease treatment, with autologous transplants being the most pronounced. Josephson et al concluded that children were at higher risk of bleeding over a wide range of platelet counts, indicating that this increased bleeding risk was likely due to factors other than the platelet counts.

On the surface these data appear surprising because most hospitals that transfuse pediatric subjects employ specific dosing with a mL/kg or random donor equivalent/5-10 kg whereas adults often receive a single apheresis unit defined as > 3 × 10¹¹ platelets/unit (AABB Standards for Blood Banks and Transfusion Services² ). Thus, adults in a population with increasing body mass with successive generations could lead to “underdosing” in larger patients and increased bleeding due to relatively fewer platelets given per transfusion. In direct contrast, the PLADO analysis did not demonstrate that bleeding correlated with (1) the morning platelet count, (2) prophylactic platelet dose, or (3) that pediatric patients would benefit from a higher prophylactic transfusion trigger, suggesting that factors other than platelets appear to impart the bleeding risk in children. These factors likely include the treatment intensity as illustrated by the most pronounced bleeding differences in children receiving autologous HSCTs (vs adults) because the former received “conditioning” regimens for solid tumors, specifically neuroblastoma, brain tumors, and Wilms tumor, while the adults received pretransplant treatment for multiple myeloma or lymphoma. When analyzed against the other children in this study in the different disease categories, the children who underwent autologous/syngeneic HSCT had similar to increased bleeding risk whereas the adults who received autologous/syngeneic HSCT had markedly lower risk of bleeding than the other adult patients in the different treatment groups. Chemotherapy-induced mucositis may also have increased bleeding risk in children because they experienced more oral, nasal, and gastrointestinal bleeding versus adults who had more skin, soft tissue, and musculoskeletal bleeding.

Children are different from adults because they tolerate more intensive chemotherapy, may have discordant structure and function of their vascular endothelium, and may have different rates of vascular regeneration after treatment-based injury resulting in accelerated platelet consumption and increased bleeding events.^3,–5  Josephson et al appropriately allude to these differences; however, other factors may impart bleeding risks including fevers, infection, and graft-versus-host disease (GVHD). The PLADO study design precluded GVHD because it was initiated immediately after HSCT, and patients were followed to day 36, which would be prior to when most patients develop GVHD, although 3 patients did manifest GVHD, which was likely acute GVHD. In addition, allergic rhinitis as a cause of epistaxis independent of platelet count was not studied and although it may represent the cause of epistaxis for many children, it would likely not impact the PLADO data because significant myelotoxicity is known to decrease allergic and atopic reactions. Future randomized controlled trials should account for the possible increased bleeding risks in febrile or infected patients as well as the effects of GVHD and aggressive treatment regimens for solid tumors, especially in pediatric patients, and must increase the sample size to ensure robust statistical analyses of the data.