Determination of the Optimal Prophylactic Platelet Dose Strategy to Prevent Bleeding in Thrombocytopenic Patients (PLADO)
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July 2004-Janury 2008
May 30, 2017
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To evaluate the effect of prophylactic platelet transfusion dose on bleeding in patients with hypoproliferative thrombocytopenia.
The optimal number of platelets in a prophylactic platelet transfusion is controversial. Platelet transfusions are costly, and require effective management for current and future supply needs. Furthermore, platelets transfusions have multiple severe, and potentially fatal, adverse outcomes. Current guidelines for a standard adult dose are approximately 3x1011 to 6x1011 platelets. Higher doses than the current guidelines are likely to result in superior hemostasis. Conversely, dosages lower than the current guidelines might be equally effective at achieving hemostasis, but more effective for cost and supply management. Previous trials with limited enrollment compared a low platelet dosage to the standard dosage. In both trials, there was no significant difference found between the dosages for prevention of bleeding.
The PLADO trial was conducted to better understand the effects of platelets dosage in prophylactic transfusion on clinical signs of bleeding, the use of platelet and red-cell transfusions, changes in the recipient’s post-transfusion platelet count, days to next transfusion, and adverse events.
Between 2004 and 2007, 1351 patients were enrolled at 26 sites. Of these, 453 patients were randomized into the low-dose prophylactic arm, 449 patients were randomized into the medium-dose prophylactic arm, and 449 patients randomized into the high-dose prophylactic arm.
Eligible subjects for the study included male and female patients of any age who weighed between 10kg and 135 kg. Patients were undergoing, or had completed, hematopoietic stem cell transplantation, for any diagnosis; or had a diagnosis of acute or chronic leukemia, non-Hodgkins or Hodgkins lymphoma, myeloma, myelodysplasia, or non-hematologic malignancy and were undergoing, or had completed, chemotherapy. Patients had, or were expected to have, hypoproliferative thrombocytopenia (platelet count ≤ 10,000/mL3) for at least 5 days. Additional criteria included prothrombin and partial-thromboplastin ≤ 1.3 times the upper limit of the normal range, a fibrinogen level ≥ 100mg/dL, and no previous platelet transfusions for thrombocytopenia during the current period of hospitalization.
Participants were excluded from the trial for safety issues, exceeding platelet count inclusion criteria, use of platelet growth factors and other related medications, pregnancy, and surgeries or other major chronic illnesses that interfered with participation based on the judgement of the study physicians.
Patients were randomly assigned to receive platelet transfusions of one of three doses: low-dose (1.1 x 1011/m²), medium-dose (2.2 x 1011/m²), or high-dose (4.4 x 1011/m²) - according to four treatment strata: allogeneic hematopoietic stem-cell transplantation, autologous or syngeneic hematopoietic stem-cell transplantation, chemotherapy for hematologic cancer, or chemotherapy for solid tumor. Dosage was based on the patient's body surface area and treatment-group assignments were balanced within trial sites with the use of dynamic balancing.
Platelet counts were obtained from patients every morning. The “trigger” threshold for a prophylactic platelet transfusion was defined as platelet count ≤ 10,000/mL3. The target range for the transfusion dose was ± 25% of the randomly assigned dose. Blood bank staff had access to the target dose range for each patient. The patient’s physician could change the trigger threshold or dose if required by clinical indications, with a return to study protocol as soon as possible. Additional platelet transfusions were permitted at any time, and at any dose, to treat active bleeding, or in association with an invasive procedure.
Hemostatic assessments were performed daily to identify any bleeding the patient may experience. The assessment involved a patient interview, physical assessment, and a chart review. Data on all transfusions (e.g., platelets and red blood cells), all transfusion-related events, all serious adverse events, and protocol deviations were also to be recorded.
Patient participation in the study was considered completed at: 30 days after the first platelet transfusion, after a 10-day period without a platelet transfusion, at hospital discharge, at death, or at withdrawal from the study (whichever occurred first).
The primary end point was bleeding of grade 2 or higher, as based on World Health Organization criteria. Secondary end points were the highest grade of bleeding, total number of platelets transfused, and number of platelet transfusions.
To account for the three treatment groups, two-sided P-values of <0.017 were considered indicative of statistical significance. No other adjustments were made for analyzing multiple outcomes.
Platelet doses between 1.1 x 1011/m² and 4.4 x 1011/m² had no significant effect on the incidence of bleeding in patients with hypoproliferative thrombocytopenia. However, patients had a 25% risk of having grade 2 or higher bleeding on days on which the morning platelet count was 5,000/mL3 or lower, as compared with a 17% risk on days with counts of 6,000-80,000 /mL3. Additionally, the low platelet transfusion dose led to a decreased number of platelets transfused per patient, but an increased number of transfusions given.
Slichter SJ, Kaufman RM, Assmann SF, et al. Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage. The New England journal of medicine. 2010;362(7):600-613. doi:10.1056/NEJMoa0904084.
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- Data Dictionary (PDF - 614.0 KB)
- Forms (PDF - 5.3 MB)
- Protocol (PDF - 258.8 KB)
- Publications (PDF - 28.0 KB)
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