Thrombopoietin (TPO) Levels in Inflammatory Disorders with or without Reactive Thrombocytosis.

TPO, the primary regulator of megakaryopoiesis, is produced at a constant rate and is removed from the circulation by adsorption to specific receptors on platelet and megakaryocyte surfaces. An inverse relationship between platelet count and TPO therefore exists in healthy subjects. However, a few studies in patients with reactive thrombocytosis identified levels of the hormone higher than expected, and suggested that TPO behaves as an acute-phase protein and was responsible for increased platelet count. At the opposite, other studies did not find any significant rise of the hormone in patients who similarly developed reactive thrombocytosis.

To gain further information on this topic, we compared TPO levels and platelet counts in two series of hospitalized patients: one (53 patients aged 73 ± 17 years) with strong elevation of both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and the other (28 age-matched control patients) with normal values. All subjects had been admitted to hospital for acute illnesses: infections, cancer, heart failure or ischemia, stroke, deep vein thrombosis or pancreatitis. Within the group of subjects with high ESR and CRP, 38 had normal platelet counts, while 15 had thrombocytosis at the admittance (n=9) or developed it during their stay (n=6). No thrombocytosis was observed in control patients. Patients with high acute phase indexes had significantly higher TPO levels (R&D Systems, Minneapolis, USA) and platelet counts than control patients (TPO 189.55pg/ml ± 139 vs 62.04pg/ml ± 83, p<0.0001; platelets 310×10⁹/L ± 98 vs 242×10⁹/L ± 67, p=0.0016). Since similar TPO and platelet values were found in patients grouped according to their disorders, we assumed that the acute phase, but not the basic illness, was responsible for the increase of TPO and platelets. We identified strong, positive correlations between ESRc (ESR corrected for Hct) and CRP (r=0.809, p<0.0001), but only weak correlations between TPO and CRP (r=0.584, p<0.0001). Interestingly, no significant relationship between platelet counts and TPO levels (r=0.180, p=NS) was find. When we grouped patients with acute-phase reaction according to absence (platelets 280×10⁹/L ± 61) or presence (platelets 516×10⁹/L ± 105) of thrombocytosis, we found similar TPO values (184pg/ml ± 146 vs 203.4pg/ml ± 126, p=NS). By measuring plasma glycocalicin (GC, Takara Bio Inc. Shiga, Japan) and estimating the glycocalicin index (GCI, by normalizing GC levels for the individual platelet count), which reflects platelet turnover, we excluded that shortened platelet survival masked increased platelet production in subjects with inflammatory conditions and normal platelet count. In fact, identical values of GCI were found in patients with normal platelet count or thrombocytosis (2.434 ± 1.4 vs 2.496 ± 2.5). Finally, no correlation was detected between TPO and GCI (r=0.003, p=NS). Conversely, a strong positive correlation between IL-6 (R&D Systems) and CRP (r=0.692, p<0.0001), and a trend towards correlation between platelet count and IL-6 (r=0.493, p<0.0001) and between TPO and IL-6 (r=0.484, p<0.0001) have been identified. All together our results confirm that TPO acts as an acute phase protein but exclude the possibility that it is uniquely responsible for thrombocytosis of inflammatory disorders, which might recognize in IL-6 a credible candidate as a cooperating factor.