Plasma Vascular Endothelial Growth Factor (VEGF) Levels Correlate with Thrombocytopenia of Various Etiology

The mechanisms leading to thrombocytopenia include (1) decreased platelet production; (2) splenic sequestration due to splenomegaly; and (3) increased peripheral consumption and/or destruction. VEGF, physiologically secreted by endothelial cells, is also produced in the alpha-granules of platelets. VEGF measured in plasma will presumably reflect its level in in vivo circulation, released from both endothelial cells and platelets. We hypothesized that thrombocytopenic disorders characterized by increased platelet destruction would manifest with increased plasma VEGF level; whereas disorders characterized by decreased platelet production or platelet sequestration would show low or normal plasma VEGF level.

Methods: This is a prospective study approved by IRB. Patients were eligible if they had platelet counts less than 150,000/ul at diagnosis. Plasma and serum specimens were collected at baseline and multiple time points towards recovery, and VEGF levels were determined using commercial ELISA kit from RayBiotech and BioRad according to manufacturer’s instructions. We enrolled 69 patients and 50 were included in the analysis. Nineteen patients were excluded from the analysis due to the following: the specimen was yielding non detectable serum VEGF value, or higher plasma VEGF level than serum level (both of above were used as internal controls for the validity of the experiment), or platelet count more than 150,000/ul. Five healthy controls were also enrolled.

Results: Among the patients, the diagnoses were (A) 18 with ITP, (B) 13 with sepsis, (C) 4 with TTP, (D) 6 with MDS or AML (E) 6 with splenomegaly and (G) 3 with gestational thrombocytopenia. There was wide inter-patient variation in each group. The inter-experiment variation on the same specimen was less than 30% in most of the cases. The mean plasma VEGF value in the ITP, sepsis, TTP and groups were 49.2 ± 36.1 ng/ml, 158.9± 380.5 ng/ml, 204.5±222.6 ng/ml respectively, and were statistically higher than that of the control group 9.1±18.1 ng/ml, (p= 0.032, 0.029 and 0.022 respectively, Mann-Whitney test). On the other hand, the mean plasma VEGF value in the MDS, splenomegaly and gestational thrombocytopenia groups were 29.8±49.1 ng/ml, 13.2±21.3ng/ml and 3.0±1.8 ng/ml respectively, similar to that of the control group (p> 0.05 in all three groups, Mann-Whitney test). One patient in the sepsis group showed an extremely high plasma VEGF value (1447 ng/ml).

Conclusion: Plasma VEGF value is a potential biomarker which can aide in the differential diagnosis of thrombocytopenia of various etiologies. Plasma VEGF levels were increased in most patients with thrombocytopenia from ITP, sepsis and TTP, but not in patients who have thrombocytopenia from MDS, splenomegaly or gestational thrombocytopenia. The elevation of plasma VEGF in those conditions could be due to increased epithelial production or release from platelet activation or destruction, the differentiation of which will need further study. A larger scale study is warranted to confirm the above result.