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Diffuse alveolar hemorrhage after HCT
Discussion
We observed that even in this recent era, the overall incidence of DAH was 5% for all patients, similar to the incidence recorded in earlier studies.5,20,21 We found that myeloablative TBI, UCB HCT, and delayed engraftment or graft failure were significant risk factors for DAH.
Thrombocytopenia is important in hemorrhagic com- plications after allogeneic HCT;22,23 however, its impor- tance in DAH is controversial.15,24,25 The relation of platelet recovery with DAH is not direct. In our study, both the severity and duration of thrombocytopenia were significantly associated with DAH. However, the risks of DAH cannot be fully explained solely by low platelet counts given that the median platelet count was >20x109/L in our patients with DAH. Robbins et al. also showed that platelet transfusions did not prevent the development and/or progression of DAH.15 Patients with DAH more often had malignant disease and myeloabla- tive conditioning, but reduced intensity conditioning was not associated with DAH.
We also found that myeloablative conditioning con- taining TBI was a risk factor for DAH. These findings strongly suggest that direct lung injury at the time of con- ditioning by myeloablative dose TBI predisposes to DAH after HCT. Others have suggested that irradiation induces cellular damage and plays an important direct
role in lung injury26 and the association with high-dose TBI during conditioning contributes to the risk of DAH.15,26-28 Moreover, TBI-induced lung injury may pro- long or deepen thrombocytopenia given that in human and some animal studies the lung can contribute to platelet production.29-31 TBI may also damage the vascular and rheological microenvironments of the pulmonary capillaries which may be more hemostatic than the microenvironments of pulmonary epithelial tissues.32
A longer duration of thrombocytopenia was associated with increased DAH in our study. It is well-known that UCB HCT is associated with delayed engraftment/graft failure compared with other related or unrelated grafts.12,15,33-35 Moreover, UCB HCT recipients also received more myeloablative conditioning with TBI, another risk factor for DAH. Overall, we found that UCB grafts were associated with more DAH than PB/BM grafts. In multi- variate analysis, UCB HCT was confirmed as an inde- pendent risk factor for DAH.
Delayed neutrophil engraftment was another risk factor for DAH, particularly for patients receiving PB/BM grafts. It is known that a higher number of stem cells/total nucle- ated cells expedites engraftment.36 Patients with DAH received fewer total nucleated cells and more often had delayed engraftment than patients without DAH in both the UCB and PB/BM HCT recipients. Among the patients undergoing single unit UCB HCT, the association
Table 3A. Multivariate analysis of risks for diffuse alveolar hemorrhage: neutrophil engraftment.
All HCT
UCB HCT
PB/BM HCT
RR P value
Variables
Conditioning RIC
MAC no TBI MAC TBI
Graftsource BM/PB UCB
ANC engraftment* Yes
No
HR (95% CI)
1.00
0.83 (0.36-1.93) 1.80 (1.03-3.13)
1.00
2.08 (1.16-3.74) 1.00
2.16 (0.93-5.01)
P value 0.05
HR (95% CI)
P value 0.08
(99% CI)
1.00
1.08 (0.28-4.16) 1.63 (0.62-4.31)
1.00
0.69 (0.23-2.04) 1.87 (0.95-3.71)
0.60
0.01 -- -- -- --
0.07
--
-- 1.00
1.57 (0.53-4.62)
0.41
P value 0.08
--
-- 1.00
5.51 (1.26-24.00)
0.02
*As a time-dependent variable.
Table 3B. Multivariate analysis for diffuse alveolar hemorrhage: platelet engraftment.
All HCT
UCB HCT
PB/BM HCT
RR P value
Variables
Conditioning RIC
MAC No TBI MAC TBI
HR (95% CI)
1.00
0.78 (0.34-1.79) 1.76 (1.02-3.04)
P value 0.05
HR (95% CI)
(99% CI)
1.00
1.10 (0.32-3.80) 1.64 (0.62-4.32)
1.00
0.65 (0.22-1.91) 1.78 (0.91-3.48)
0.60
Graftsource 0.07 -- -- -- --
BM/PB
UCB
Platelet engraftment* Yes
No
1.00
1.65 (0.96-2.83) 1.00
4.44 (2.10-9.42)
<0.01
--
-- 1.00
6.96 (2.39-20.29)
<0.01
--
-- 1.00
2.26 (0.74-6.90)
0.15
*As a time-dependent variable. ANC: absolute neutrophil count; BM: bone marrow; HCT: hematopoietic stem cell transplantation; HR: hazard ratio; MAC: myeloablative condi- tioning; PB: peripheral blood; RIC: reduced intensity conditioning; TBI: total body irradiation; UCB: umbilical cord blood.
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