Program: Oral and Poster Abstracts
Session: 101. Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron: Poster I
Methods: 165 patients with CP were enrolled in a registry between 2001 and 2009 after providing written informed consent. Survival analysis was used to examine the predictors of new thrombosis and death during the follow-up period. mRNA from peripheral blood mononuclear cells (PBMCs) was profiled by Affymetrix Human Exon 1.0 ST Array in 42 of the subjects.
Results: The median age at enrollment was 35 years and 90 participants were females, 25 had a history of one thrombosis, 5 of two thromboses and 3 of three thromboses. In the year prior to study entry, 72 had received phlebotomy therapy (Table 1). In July 2015 the median follow-up was 9.0 years (range 1-14.5). During this follow-up period, 30 (18.2%) participants had one new thrombosis, 6 (3.6%) had two new thromboses and 17 (10.3%) died. The median age of death was 55 years (range 16-76) and deaths were related to thrombotic cerebrovascular accident (n = 4), myocardial infarction (n = 4), mesenteric or portal vein thrombosis (n = 3), other major thromboembolic events (n = 2) and trauma or unknown cause (n = 2). Baseline characteristics of older age, prior thrombosis, pentoxifylline treatment, smoking and splenomegaly were independently associated with greater thrombosis risk during follow-up (P < 0.003). After adjustment for these variables, the estimated probability of new thrombosis at 10 years was 26% in those receiving phlebotomies compared to 12% in those not phlebotomized (log rank P = 0.014) (Figure 1). There was also a trend for increased risk of death with phlebotomy: estimated probability 8.7% versus 3.7% (P = 0.15). Examination of gene transcripts affecting thrombosis by logistic regression identified 12 protective and 16 risk genes at 5% false discovery rate. Upregulation of two mRNAs was of singular significance: 1) IL1RAP, a proximal signaling adaptor of IRAK1 (Immunity 1997, 7: 837) and 2) THBS1, encoding thrombospondin1 (Blood 2015, 125: 399). Both genes have known roles in thrombosis promotion and we previously reported that THBS1 is upregulated in CP (BCMD 2014, 52:35). Further analysis revealed a further upregulation of THBS1in patients with baseline history of phlebotomy (β=0.41, P=0.046).
Conclusion: These findings underscore a high rate of thrombosis and death in patients with CP and reveal a potential role of increased IRAK1/IL1RAP signaling in these complications. They raise the possibility that phlebotomy therapy has a detrimental rather than beneficial effect, possibly contributed to by increased THBS1 expression.
Table 1- Baseline characteristics by phlebotomy in the year prior to enrollment. Results in median (interquartile range) or n (%); four without phlebotomy data. |
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|
No phlebotomy N=89 |
Received phlebotomy N=72 |
|
Age (years) |
32 (18-48) |
37 (26-49) |
0.08 |
Female gender, n (%) |
52 (58%) |
34 (47%) |
0.16 |
Smoking, n (%) |
18 (20%) |
24 (33%) |
0.060 |
History of thrombosis, n (%) |
20 (23%) |
12 (17%) |
0.4 |
Splenomegaly, n (%) |
2 (2.3%) |
2 (2.8%) |
0.8 |
ASA treatment, n (%) |
27 (30%) |
36 (50%) |
0.011 |
Pentoxifylline, n (%) |
7 (7.9%) |
17 (23.6%) |
0.005 |
BMI (kg/m2) |
20.4 (18.3-22.9) |
21.6 (19.9-24.6) |
0.010 |
Systolic BP (mm Hg) |
109 (100-123) |
118 (105-124) |
0.6 |
Diastolic BP (mm Hg) |
76 (68-84) |
78 (71-83) |
0.8 |
Hemoglobin (g/dL) |
18.1 (16.4-21.0) |
17.9 (16.0-19.8) |
0.5 |
WBC (per uL) |
5.7 (4.6-7.0) |
5.5 (4.6-6.7) |
0.9 |
Figure 1.
Disclosures: No relevant conflicts of interest to declare.
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