American Journal of Hematology 39:183-187 (1992)

Increased Levels of Plasma Thrombomodulin in Chronic Myelogenous Leukemia Eriko Morishita, Masanori Saito, Hidesaku Asakura, Hiroshi Jokaji, Chika Uotani, lchiro Kumabashiri, Masahide Yamazaki, and Tamotsu Matsuda Department of Internal Medicine (Ill), Kanazawa University School of Medicine, Kanazawa, Japan

Circulating blood plasma contains proteinase-degradedforms of thrombomodulin that are soluble. We quantitatively assayed the plasma levels of thrombomodulin in 15 patients with chronic myelogenous leukemia (CML) in chronic phase by method of an enzymelinked immunosorbent assay using a monoclonal antibody to protease-degradedproducts of thrombomodulin. Plasma levels of thrombomodulin in patients with CML at diagnosis were significantly increased (19.5 2 6.2 ng/ml: means f SD) compared with the levels in normal controls (8.0 -c- 1.9 nglml, n = 20) (P < 0.001). Fibrin degradation products (D-dimer), thrombin-antithrombin 111 complex, and plasmin a,-antiplasmin complex were almost normal, suggesting that intravascular coagulation or plasmin-mediatedfibrinolysis little occurred in these patients. On the other hand, the plasma levels of elastase-a,proteinase inhibitor (E-@,PI) complex, which was the indicator of released leukocyte elastase, were significantly increased in CML (P < 0.0001). The plasma levels of thrombomodulin and E-a,PI complex were decreased in parallel with decline of leukocyte counts in 10 patients with CML following anti-leukemic therapy. Furthermore, a statistically significant correlation was observed between the plasma levels of thrombomodulin and E-a,PI complex obtained at 39 time points in 15 patients with CML (r = 0.81, P < 0.001). These results suggest that the increasedplasma levels of thrombomodulin in CML may be partly caused by leukocyte elastase, which may split the surface thrombomodulin and release protease-degradedfragments of it into the circulation. Key words: leukocyte elastase, plasma thrombomodulin, protease-degradedfragments

INTRODUCTION

Thrombomodulin is a constituent glycoprotein on the endothelial cell surface that serves as a receptor of thrombin [ 1,2]. Thrombin bound to thrombomodulin activates protein C, and then activated protein C inactivates blood coagulation cofactors, factor Va and VIIIa [3-51. In addition, human thrombomodulin also inhibits factor Xa activity in the prothrombinase complex [6]. Thus, thrombomodulin plays an important role as an anticoagulant protein on the blood vessel wall [7]. Although thrombomodulin is mainly present on endothelial cell surfaces, thrombomodulin is also found in circulating blood plasma [8]. It has been suggested that plasma thrombomodulin is released from endotheiial cell membrane by its injury and removed from the circulation mostly by the kidney and liver. previous studies have shown that plasma levels Of thrombomodulin are increased in Various diseases with Or without intraVaSCUlar coagulation, e.g., disseminated intravascular coagulation 0 1992 Wiley-Liss, Inc.

syndrome (DIC) [9], pulmonary thromboembolism, adult respiratory distress syndrome (ARDS), chronic renal failure, acute hepatic failure [ 101, or diabetic angiopathy [ 111. The increase of plasma thrombomodulin found in these diseases is mainly due to an increase of the protease-degraded forms of thrombomodulin [ 101. Human polymorphonuclear leukocyte elastase is the major neutral protease released from leukocytes. Since the enzyme rapidly binds to plasma inhibitors such as a,-proteinase inhibitor and a,-macroglobulin, increased elastase-a, -proteinax inhibitor (E-a,Pl)complex in plasma would be an indication of elastase liberation from leukocytes [ 12,131. Several studies have indicated that

Received for publication April 4, 1991; accepted September 26, 1991. Address reprint requests to Eriko Morishita, Department of Internai Medicine ( I I ~ ) , Kanazawa University School of Medicine, 13Takaramachi, Kanazawa 920, Japan.

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leukocyte elastase is released into the circulation in leukemia and in sepsis [ 14,151, and the decreased concentrations of coagulation factors in plasma or the increased levels of fibridfibrinogen degradation products (FDP) in serum seen in these conditions may be the result of leukocyte elastase-mediated proteolysis of coagulation factors of fibrinogen and/or fibrin [14,16,17]. In view of these previous reports, we measured plasma levels of thrombomodulin in patients with chronic myelogenous leukemia (CML) who had elevated levels of leukocyte elastase, and investigated the relationship between plasma thrombomodulin and leukocyte elastase.

MATERIALS AND METHODS Collection of Blood Samples

TABLE 1. Laboratory Data of Normal Controls and Patients With CML*

CML (n = 15)

Control (n = 20)

106.6 f 83.4 13.2 f 0.9 39.9 f 7.2 249 f 45 1 1 . 1 f 7.9 0.5 0.3 2.2 0.8 0.7 0.5 743 f 415

6.0 f 1 . 1 12.9 f 1.0 34.3 f 2.2 236 f 37 2.2 f 0.4 0.3 f 0.3 2.3 f 0.7 0.4 0.2 67 f 44

P value

~~~

WBC (X 103/pl) PT (sec) APTT (sec) Fibrinogen (mgldl) FDP (pglml) D-dimer (pglml) TAT PIC (pg/ml) E - ~ I P(ue/l) I

* * *

+

Increased levels of plasma thrombomodulin in chronic myelogenous leukemia.

Circulating blood plasma contains proteinase-degraded forms of thrombomodulin that are soluble. We quantitatively assayed the plasma levels of thrombo...
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