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Increased Soluble Thrombomodulin Does Not Always Indicate Endothelial Injury

To the Editor: In a recent article published in this journal, Mori and colleagues (1) reported increased levels of plasma soluble thrombomodulin (TM) in patients with thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). They also found the TM levels to be higher in patients who died compared with those who survived. No such differences were noted for increased circulating von Willebrand factor, tissue plasminogen activator (tPA), type 1 plasminogen activator inhibitor (PAI-1), tPA-PAI-1 complex, and granule membrane protein-140. The authors concluded that of the previous markers of systemic vascular endothelial cell injury, only the soluble TM levels were predictive of the outcome of thrombotic microangiopathy. The study by Mori and coworkers (1) seems to have missed important information on liver and renal function as predictors of both the increased TM levels and death in their patients. From the clinical point of view, it is expected that some degree of liver dysfunction was present in the patients studied because 15% of them had underlying advanced neoplastic disease treated with cytotoxic drugs, which in concert with TTP/HUS were likely to result in liver damage. Moreover, an unspecified number of the participants had overt renal failure on admission or at the onset of TTP/HUS. Plasma creatinine levels up to 2.0 mg/dL mean that their glomerular filtration rate was reduced to about 50% of normal. Diseased liver is a recognized modulator of soluble TM levels (2-6). Viral hepatitis (4) and acute liver damage (5) are associated with enhanced expression of TM in hepatic sinusoidal endothelial cells, and its subsequent release into the blood. Immunohistochemical studies of injured hepatic tissue (3,5) showed that both TM reactivity on the endothelial surfaces and circulating TM levels paralleled the extent of parenchymal damage and regeneration of the liver. Enhanced TM expression in hepatic endothelial cells (7) as well as high TM levels in peripheral blood (8,9) and vena cava effluents (7,8) were also reported in transplanted patients with poor liver graft function. The increase in plasma TM levels during the course of liver disease may also be due to defective hepatic degradation of the circulating glycoprotein. Although this process has not been adequately studied in humans, the liver appears to be an important site of TM clearance in experimental animals (10). It is not known how profoundly liver dysfunction influences soluble TM levels. Akiyama and coworkers (3) found no correlations between increased circulating TM and conventional liver function tests in patients with various liver disorders. This could be due to the well-established fact that plasma TM levels are also strongly dependent on renal excretory function (11-13). Recently, we showed (13) that reduction in creatinine clearance from 100 mL/min to 10 mL/min resulted in an increase of about 3.2 ng/mL (80%) in soluble TM levels in 38 conservatively treated renal patients without evidence of liver dysfunction (Fig. 1A). At the same time, we found no correlation between plasma TM concentration and degree of proteinuria, which is a marker of increased permeability of the glomeruli. The increase in serum creatinine levels from 1.4 mg/dL (an upper limit of laboratory range) to 2 mg/dL, as was the case in some of the patients studied by Mori and coworkers (1), is likely to produce the significant increment of about 35% in the soluble TM level (Fig. 1B). On the other hand, we also showed (6) the strong direct association between the rise in a hepatocellullar injury marker serum alanine aminotransferase (ALT) activity and soluble TM levels in maintenance hemodialysis patients. Regression analysis of our data obtained in 138 mostly anuric hemodialysis patients (Fig. 1C) indicates that an increment in serum ALT activity from 5 IU/L to 50 IU/L, which is still within the reference range, results in an increase of about 5 ng/mL (70%) in the TM level. This increase exceeds 100% when the ALT level rises above 100 IU/L.