This present study investigated the plasma levels of sP-selectin, a marker of platelet and endothelial activation, and F1 + 2, a marker of early phase of thrombosis, in 17 controls and 38 patients with AML and CML.
P-selectin is an adhesion molecule stored in Weibel-Palade bodies of endothelial cells and alpha-granules of platelets. It is the largest of the known selectins, along with E-selectin (expressed by endothelial cells) and L-selectin (expressed by leukocytes).8,12 Several studies reported that acute leukemia are related to higher platelet activation. Mechanisms leading such activation are: (1) leukemic cells cause endothelial cells damage while invading bone marrow, body tissues, and organs; (2) leukemic cells release procoagulant molecules; (3) leukemic cells express adhesion molecules; (4) chemotherapeutic agents cause endothelium damage; (5) leukemic cells release higher levels of cytokine and chemokines.13 Cytokines released by blast cells can induce the expression of P-selectin.8
Upon activation, P-selectin is mobilized to the external membrane to mediate leukocyte adherence.8,12 Role of P-selectin in coagulation cascade can be explained by two ways. First, P-selectin may support platelet-platelet interaction. Secondly, P-selectin on platelet surface promotes leukocyte recruitment and facilitates binding of tissue factor-bearing microparticles (TF-MP), derived from normal cells or cancer cells, to leukocytes via PSGL-1.8,14,15 Additionally, adhesion of leukocytes to P-selectin via PSGL-1 induces shedding of P-selectin into the circulation. Increased concentrations of soluble form of P-selectin (sP-selectin) from activated platelets or activated endothelial cells are associated with VTE events in cancer patients.16,17 A possible mechanism is that sP-selectin can activate leukocytes via PSGL-1 to generate TF-MP which contribute to pro-coagulant state.11,18
In the present study, plasma levels of sP-selectin were increased significantly in CML patients in relation to AML patients and controls. This findings were supported by Cella et al who demonstrate a significant increased levels of sP-selectin in myeloproliferative neoplasms (MPN) patients compared to controls.12 Furthermore, this might be related to higher platelet counts in CML patients than in AML patients, as seen in our patients (median 417x103/mm3 vs. 67x103/mm3, p < 0.05). Leinoe et al clarified that low P-selectin expression on stimulated AML platelets are due to reduced platelet synthesis as well as alpha-granules dysfunction.19 Platelet abnormalities and/or dysfunction have also been reported in CML patients. However, this may be of particular importance in AML patients as AML is a rapidly progressive disease with severe quantitative platelet defect.20,21
In our study, both AML and CML patients had increased concentrations of F1 + 2 in relation to controls (p < 0.05). These results are similar to a study by Negaard et al. They found that the baseline values (before cancer therapy) of F1 + 2 were increased among of patients with hematological malignancies, including AML, compared to controls. Levels of F1 + 2 in plasma decreased significantly after cancer treatment (median 281.8 pM vs. 258.6 pM, p = 0.03), but remained significantly higher than controls (median 258.6 pM vs. 1.3 pM, p < 0.001).22 Thus, the state of hypercoagulability in myeloid malignancy is high at baseline and even after termination of cancer treatment.
Moreover, sP-selectin was positively correlated to leukocyte count and F1 + 2 (p = 0.029 for both) only in AML patients, reflecting the interplay between platelet and/or endothelial activation and inflammation. This agrees with Wakefield and Myers who demonstrated that thrombosis and inflammation are inter-related.23 Indeed, high leukocyte count in leukemia are associated with higher incidence of vascular complications. One potential mechanism to support this concept is that leukemic cells are able to activate endothelial cells via various cytokines, such as tumor necrosis factor alpha (TNF-α). Subsequent attachment of leukemic cells to the vessel wall via adhesion molecules induces coagulation activation and leukocyte aggregation.24 This is supposed to explain the correlation between leukocyte count and sP-selectin as well as sP-selectin and F1 + 2 in AML patients of our study. Differently, in CML patients, plasma sP-selectin levels were not correlated with leukocyte count and F1 + 2. It might be possible that we could not detect direct correlation between those biomarkers because of the small group of CML patients.
On the other hand, PSGL-1 is predominantly expressed on myeloblast (AML blasts) rather than lymphoblast to interact with either P- or E-selectins. It is not only able to induce coagulation activation, but also promoting blast cells survival, drug resistance, and metastasis.8,25 Thus, inhibiting selectins interaction with their ligands may provide a new promising thromboprophylaxis, especially in AML in patients who carry high risk of bleeding during anticoagulant due to severe thrombocytopenia.
Some limitations of this study need to be acknowledged: (1) significant results may be hampered by a relatively small sample size; (2) we did not consider other congenital or acquired thrombophilia that might contribute to thrombotic risk. However, the results of this study may serve as a basis for future observational or interventional studies on thromboprophylaxis in hematological malignancies.