Enhanced generation of monocyte tissue factor and increased plasma prothrombin fragment1+2 levels in patients with polycythemia vera: Mechanism of activation of blood coagulation

Abstract

Polycythemia vera (PV) is associated with a high incidence of thrombosis. The association of apparent and secondary polycythemia with thrombosis is not clear. It was suggested that activation of the coagulation system contributes to thrombus formation in PV. However, the mechanism of activation is unknown. Monocytes generate a potent tissue factor (TF) upon stimulation with various substances, which is involved in thrombus formation in various disorders. Therefore, we studied the possibility that the factor is involved in the activation of coagulation and thrombus formation also in PV. Unstimulated peripheral blood mononuclear cells (PBMC) from each of the different types of polycythemia expressed weak TF activity (2 U) and antigen (41.4 to 52.9 pg/ml), which were similar to normal controls. Following stimulation with endotoxin, PBMC from normal controls and from apparent and secondary polycythemia showed a 3.9-to 4.5-fold increase in TF, while cells from PV showed a 21-fold increase (P < 0.001). Similar levels were generated by PBMC after treatment of PV and at the spent phase. TF was generated by monocytes but not by lymphocytes. Plasma prothrombin fragment 1+2 (F 1+2 ) levels, assayed at the same time, were significantly higher in PV (2.46 nm) compared to normals and apparent and secondary polycythemia (0.22 to 0.32 nm), and were in a significant correlation with monocyte TF activity and antigen levels (r = 0.77, 0.87). The high levels of F 1+2 confirm that the coagulation system is activated in PV. The increased capacity of monocytes to generate TF may be responsible for the activation of the coagulation system and thrombus formation. The hypercoagulability state that is induced by this mechanism suggests that long-life oral anticoagulation should be considered once thrombosis has been developed in PV. Am.

Prevalence of Venous Thromboembolism in Patients With Secondary Polycythemia

“…Obstructive sleep apnea (OSA), obesity hypoventilation syndrome, and chronic obstructive pulmonary disease (COPD) are the most common causes of hypoxemia, leading to secondary polycythemia. The degree to which laboratory markers of coagulation activation are elevated is substantially less in secondary polycythemia than in PV, 9 and there is no clear clinical evidence that secondary polycythemia poses an elevated thrombosis risk. Nevertheless, we have observed that cytoreduction with phlebotomy is frequently recommended for secondary polycythemia patients, likely extrapolating from the PV model.…”

Elevation of plasma tissue factor levels in patients with severe acute pancreatitis

“…Because proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α are known to be elevated in SAP, [28][29][30] TF might be induced by monocytes/macrophages in response to these mediators or an endotoxin. 31,32 Furthermore, these mediators induce vascular endothelial injuries in SAP, and endothelial cells can induce TF. 33,34 In our study, however, plasma TF levels were not significantly correlated with serum levels of proinflammatory cytokines on admission.…”

Polycythemia Vera

“…Carvalho and associates demonstrated in 12 of 17 patients with PV, low levels of factor XII, prekallikrein, and kallikrein inhibitor, suggesting that activation of the intrinsic coagulation system occurred in PV patients.&dquo; Kornberg and associates also confirmed that the coagulation system is activated by demonstrating that prothrombin fragmentl+2 levels, a peptide which is released when prothrombin is cleaved by factor Xa, were higher in PV. 17 However, the pathogenesis of activation of the blood coagulation system is unknown. To address this issue, Kornberg and colleagues also examined tissue factor levels and demonstrated a 17-fold increase in tissue factor (TF) generation in peripheral blood mononuclear cells stimulated by endotoxin from PV patients when compared to control subjects.17 The increase in TF levels was not due to increased platelet satellitism, which has been shown to occur in PV and other myeloproliferative disorders.…”