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Predicting bleeding in thrombocytopenic neonates
Discussion
In this study, we developed a dynamic prediction model for major bleeding in thrombocytopenic preterm neonates. The model has a good predictive performance with a median c-index of 0.74. To our knowledge, this is the first dynamic prediction model for bleeding in preterm neonates.
The importance of using a dynamic model is illustrated by a recent survey assessing at which thresholds clinicians would administer a platelet transfusion to a preterm neonate with a gestational age of 27 weeks at birth.19 The study showed that if this neonate was 2 days old and in a stable condition, most (European) clinicians would trans- fuse at a threshold platelet count of 30x109/L. However, if the same neonate was septic, mechanically ventilated and receiving vasopressors, most clinicians would transfuse at a threshold of 50x109/L. This illustrates that although neonates may have a comparable clinical status at baseline (gestational age 27 weeks), their clinical course in the fol- lowing days is perceived as an important determinant of bleeding risk. We have developed a model that allows cli- nicians to quantify bleeding risk and adjust it as the clinical situation of the neonate changes.
Future validation studies should externally validate and preferably expand the model, to improve its predictive accuracy. Once a larger, externally validated model has been developed, it can be used to study the effect of platelet transfusion indications based on predicted risk of bleeding in an impact study. Ultimately, this is a first step towards individualized platelet transfusion guidelines. Individualized guidelines are important because several studies have shown that there is a large discrepancy between the number of thrombocytopenic neonates receiving platelet transfusions (75%) and the number of neonates who develop major bleeding (9%).5,20 These numbers are comparable to our results: 70% of neonates received transfusions and 11% developed major bleeding. In addition, results of a recent randomized trial indicate platelet transfusion-related harm when using a platelet count threshold of 50x109/L compared to 25x109/L. Although the overall results of this study showed benefit associated with the low threshold, not all neonates in the high threshold group developed major bleeding or died. Moreover, 19% of neonates in the low threshold group died or developed major bleeding. This indicates that a
Figure 2. Number of neonates reaching the different study endpoints (major bleeding, death or discharge/transfer) in the first 10 days after the onset of severe thrombocytopenia. T0 is the day on which the platelet count dropped below 50x109/L for the first time. Neonates who developed a major bleed and then died were only registered as having major bleeding (no overlap between major bleeding and mortality).
Table 2. Types of bleeding.
Major bleeds, n (%) 71 (11)
Type of major bleeding, n (%) 32 (45) Uni-/bilateral IVH grade 3 with
or without parenchymal involvement
IVH grade 1 or 2 (uni- or bilateral) 4 (6)
with parenchymal involvement
Solitary (non-cerebellar) parenchymal hemorrhage 4 (6) Cerebellar parenchymal hemorrhage 11 (15) Subdural hemorrhage 4 (6) Pulmonary hemorrhage 12 (17) Gastrointestinal hemorrhage 4 (6)
Eight bleeds (of 71) were excluded from the model because they occurred more than 10 days after T0.: one cerebellar, one IVH grade 1 plus basal ganglia infarction, one IVH grade 1 and grade 2 plus basal ganglia infarction, one gastrointestinal bleed, one pulmonary bleed, one bilateral IVH grade 3, one frontal-parietal bleed and one sub- dural hemorrhage. IVH: intraventricular hemorrhage.
platelet count-based transfusion threshold does not accu- rately separate neonates whose bleeding or death will be prevented by a platelet transfusion. A threshold that includes clinical variables, such as one based on our dynamic prediction model, might perform better and thereby improve outcomes.
It is important to note that individual covariates in the model should not be interpreted as causal associations, because the associations may be confounded in multiple ways. For example, IUGR was associated with lower pre- dicted bleeding risk in our model, but we cannot conclude that IUGR protects against bleeding. Firstly, because IUGR is also a risk factor for thrombocytopenia, and we restrict- ed our population to neonates with thrombocytopenia. It is possible that other causes of thrombocytopenia, for example viral infections, are associated with a higher risk of bleeding than that of IUGR. A neonate with thrombo- cytopenia as a result of IUGR is therefore not protected by IUGR, but has a lower bleeding risk because the thrombo- cytopenia was not caused by a viral infection. This is an epidemiological concept called collider stratification bias.21 Secondly, perhaps neonates with IUGR received more treatments intended to decrease the risk of bleeding as compared to neonates without IUGR, as neonatologists perceived them to be at higher risk of bleeding (confound- ing by indication). And lastly, because the number of events in our study was limited, we were not able to cor-
haematologica | 2019; 104(11)
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