Plasma Levels Of Soluble Thrombomodulin Research Articles

Iloprost and Organ Dysfunction in Adults With Septic Shock and Endotheliopathy

Soluble thrombomodulin is a marker of endotheliopathy, and iloprost may improve endothelial function. In patients with septic shock, high plasma levels of soluble thrombomodulin (>10 ng/mL) have been associated with worse organ dysfunction and mortality. To assess the effects of treatment with iloprost vs placebo on the severity of organ failure in patients with septic shock and plasma levels of soluble thrombomodulin higher than 10 ng/mL. This investigator-initiated, adaptive, parallel group, stratified, double-blind randomized clinical trial was conducted between November 1, 2019, and July 5, 2022, at 6 hospitals in Denmark. The trial had a maximum sample size of 380, with an interim analysis for futility only at 200 patients with 90 days of follow-up. In total, 279 adults in the intensive care unit (ICU) with septic shock and endotheliopathy were included. Patients were randomized 1:1 to masked intravenous infusion of iloprost, 1 ng/kg/min (n = 142), or placebo (n = 137) for 72 hours. The primary outcome was mean daily Sequential Organ Failure Assessment (SOFA) score in the ICU adjusted for trial site and baseline SOFA score for the per-protocol population. SOFA scores for each of the 5 organ systems ranged from 0 to 4, with higher scores indicating more severe dysfunction (maximum score, 20). The secondary outcomes included serious adverse reactions and serious adverse events at 7 days and mortality at 90 days. Of 279 randomized patients, data from 278 were analyzed (median [IQR] age, 69 [58-77] years; 171 (62%) male), 142 in the iloprost group and 136 in the placebo group. The trial was stopped for futility at the planned interim analysis. The mean [IQR] daily SOFA score was 10.6 (6.4-14.8) in the iloprost group and 10.5 (5.9-15.5) in the placebo group (adjusted mean difference, 0.2 [95% CI, -0.8 to 1.2]; P = .70). Mortality at 90 days in the iloprost group was 57% (81 of 142) vs 51% (70 of 136) in the placebo group (adjusted relative risk, 1.12 [95% CI, 0.91-1.40]; P = .33). Serious adverse events occurred in 26 of 142 patients (18%) for the iloprost group vs 20 of 136 patients (15%) for the placebo group (adjusted relative risk, 1.25 [95% CI, 0.73-2.15]; P = .52). Only 1 serious adverse reaction was observed. In this randomized clinical trial of adults in the ICU with septic shock and severe endotheliopathy, infusion of iloprost, 1 ng/kg/min, for 72 hours did not reduce mean daily SOFA scores compared with placebo. In a clinical context, administration of iloprost will be unlikely to improve outcome in these patients. ClinicalTrials.gov Identifier: NCT04123444.

Why patients with THBD c.1611C>A (p.Cys537X) nonsense mutation have high levels of soluble thrombomodulin?

BackgroundRecently our group has described a new autosomal dominant bleeding disorder characterized by very high plasma levels of soluble thrombomodulin (TM). The THBD c.1611C>A (p.Cys537X) mutation in heterozygous state was found in the propositus. This mutation leads to the synthesis of a truncated TM which has lost the last three amino-acids of the transmembrane domain and the cytoplasmic tail.ObjectiveWe investigated the mechanism responsible for TM shedding in endothelial cells with THBD c.1611C>A mutation.MethodsComplementary DNA of TM wild type (TM-WT) was incorporated into a pcDNA3.1 vector for transient transfection in COS-1 cells. Mutagenesis was performed to create the c.1611C<A (TM1-536) mutant and 4 other TM mutants (TM1-515, TM1-525, TM1-533 and TM1-537) with a transmembrane domain having different lengths. The effect of shear stress, metalloprotease inhibitor, certain proteases and reducing agents were tested on TM shedding.ResultsWestern blot and immunofluorescent analysis showed that TM1-536 was produced and a certain amount of TM1-536 was anchored on the cell membrane. A significantly higher levels of soluble TM was observed in the TM1-536 cell medium in comparison with TM-WT (56.3 +/- 5.2 vs 8.8 +/- 1.6 ng/mL, respectively, p = 0.001). The shedding of TM1-536 was 75% decreased in cells cultured in the presence of a metalloprotease inhibitor. No difference was observed between TM1-536 and TM-WT shedding after cell exposure to cathepsin G, elastase, several reducing agents and high shear stress (5000 s-1). Significantly higher levels of soluble TM were observed in the cell media of TM1-533, TM1-525, TM1-515 in comparison with TM-WT (p < 0.05).ConclusionThe mechanism responsible for TM shedding is complex and is not completely understood: higher sensitivity of the TM1-536 to the proteolysis by metalloproteases and a defect of synthesis due to the decreased size of the transmembrane domain might explain the high levels of soluble TM in plasma of the carriers.

Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study.

IntroductionThe significance of endothelial injury in children with the acute respiratory distress syndrome (ARDS) has not been well studied. Plasma levels of soluble thrombomodulin (sTM), an endothelial surface protein involved in coagulation, have been associated with endothelial injury. We hypothesized that elevated plasma sTM would correlate with mortality and organ failure in children with ARDS.MethodsWe conducted a multicenter prospective observational study of pediatric patients with ARDS between 2008 and 2014. sTM was measured in plasma collected less than 24 hours from ARDS diagnosis. Outcomes were intensive care unit mortality and organ dysfunction by pediatric logistic organ dysfunction scores. Logistic regression was used to adjust for clinically relevant covariates.ResultsPlasma sTM was higher in patients with indirect lung injury compared to direct lung injury (100 ng/mL vs. 86 ng/mL, p = 0.02). Increased sTM levels were correlated with more organ dysfunction in the entire study population (Spearman’s rho = 0.37, p < 0.01). Overall mortality was 16 %. sTM levels were associated with increased mortality in patients with indirect lung injury (OR 2.7 per log(sTM), p = 0.02). These relationships were independent of age, oxygenation defect, or presence of acute kidney injury.ConclusionElevated plasma sTM levels are associated with organ dysfunction in children with ARDS and with higher mortality in children with indirect lung injury. These findings highlight the importance of endothelial injury in children with ARDS and may guide the development of future therapies targeted toward endothelial stabilization, repair, or functional replacement in this population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1145-9) contains supplementary material, which is available to authorized users.

Soluble Thrombomodulin and Endothelial Cell Protein C Receptor Levels in Patients with Cerebral Venous and Sinus Thrombosis

Introduction: Cerebral venous and sinus thrombosis (CVST) is a potentially serious disorder. In search for underlying coagulopathy in CVST patients, we measured plasma levels of soluble thrombomodulin (sTM) and soluble endothelial protein C receptor (sEPCR) in patients with CVST as candidate biomarkers of thrombosis. Materials and Methods: The concentrations of sTM and sEPCR in 19 CVST patients without protein C and protein S deficiency were measured by ELISA and compared with 53 healthy controls. We also examined the association between those plasma markers and the risk of CVST. Results: Significant difference was identified in plasma sTM level between CVST patients and controls (0.95 ± 0.09 vs. 1.26 ± 0.12 ng/ml, respectively; p = 0.038). The plasma level of sEPCR was not different between groups, and no significant quantitative association was identified between the risk of CVST and the levels of sEPCR. The adjusted odds ratio for CVST associated with low (<10th percentile) levels of sTM was 2.3 (95% CI: 1.29-20.08; p = 0.012) after adjustment for confounding factors. Conclusion: Decreased plasma sTM concentration may be associated with an increased risk of CVST.

Hypoperfusion in Severely Injured Trauma Patients is Associated With Reduced Coagulation Factor Activity

Recent studies have shown that acute traumatic coagulopathy is associated with hypoperfusion, increased plasma levels of soluble thrombomodulin, and decreased levels of protein C but with no change in factor VII activity. These findings led to the hypothesis that acute traumatic coagulopathy is primarily due to systemic anticoagulation, by activated protein C, rather than decreases in serine protease activity. This study was designed to examine the effect of hypoperfusion secondary to traumatic injury on the activity of coagulation factors. Post hoc analysis of prospectively collected data on severely injured adult trauma patients presenting to a single trauma center within 120 minutes of injury. Venous blood was analyzed for activity of factors II, V, VII, VIII, IX, X, and XI. Base deficit from arterial blood samples was used as a marker of hypoperfusion. Seventy-one patients were identified. The activity of factors II, V, VII, IX, X, and XI correlated negatively with base deficit, and after stratification into three groups, based on the severity of hypoperfusion, a statistically significant dose-related reduction in the activity of factors II, VII, IX, X, and XI was observed. Hypoperfusion is also associated with marked reductions in factor V activity levels, but these appear to be relatively independent of the degree of hypoperfusion. The activity of factor VIII did not correlate with base deficit. Hypoperfusion in trauma patients is associated with a moderate, dose-dependent reduction in the activity of coagulation factors II, VII, IX, X, and XI, and a more marked reduction in factor V activity, which is relatively independent of the severity of shock. These findings suggest that the mechanisms underlying decreased factor V activity--which could be due to activated protein C mediated cleavage, thus providing a possible link between the proposed thrombomodulin/thrombin-APC pathway and the serine proteases of the coagulation cascade--and the reductions in factors II, VII, IX, X, and XI may differ. Preservation of coagulation factor activity in the majority of normally and moderately hypoperfused patients suggests that aggressive administration of plasma is probably only indicated in severely hypoperfused patients. Markers of hypoperfusion, such as base deficit, might be better and more readily available predictors of who require coagulation support than international normalized ratio or activated partial thromboplastin time.

Calibrated automated thrombography demonstrates hypercoagulability in patients with idiopathic pulmonary arterial hypertension

Introduction Pathogenesis of idiopathic pulmonary arterial hypertension (iPAH) includes endothelial dysfunction and in situ thrombosis. A hypercoagulable state has also been postulated but never demonstrated. Our objective was to determine whether patients with iPAH had a hypercoagulable state using calibrated automated thrombography (CAT), a new tool to phenotype coagulation in vitro. Patients and methods 16 patients with iPAH and 29 controls were studied. In vitro platelet dependent coagulation phenotyping by CAT monitored the activity of thrombin generation over time. Plasma levels of soluble thrombomodulin, tissue factor pathway inhibitor (TFPI) and von Willebrand factor (VWF) were measured as endothelial biomarkers. Results Endogenous thrombin potential (ETP) in the absence of activated protein C (APC) tended to be increased in patients compared to controls (1769 versus 1656 nM.min; p = 0.053). ETP was higher in the presence of APC 25 nM (ETP-APC) in patients (781 versus 494 nM.min; p = 0.005). Five patients had ETP-APC higher than the 95th centile of controls. Other CAT parameters (lag time, peak thrombin and time to peak) were all consistent with some degree of hypercoagulability in patients. Regarding endothelial plasma biomarkers sTM was lower (28.4 versus 40.6 μg/l, p = 0.0108) in patients; TFPI antigen and activity (respectively: 14.3 versus 10.5 μg/l, p = 0.0167; 1.155 versus 1.070, p = 0.0021) and VWF (1300 versus 976%, p = 0.0108) were higher in patients. Conclusion We have demonstrated that at least some patients with iPAH have a hypercoagulable phenotype.

Kinetics of Thrombin Generation in Patients with Multiple Myeloma.

Thalidomide has emerged as a promising treatment for multiple myeloma (MM). Thrombosis is the most serious complication of thalidomide therapy, essentially when it is combined with dexamethasone. The pathogenesis of thrombosis in MM patients (pts) treated with thalidomide is not clear and probably of multi factorial origin. We used the Thrombin Generation test (TGT) and measured the plasma levels of soluble thrombomodulin (sTM) to better clarify the MM-related and thalidomide-related thrombogenicity. TGT was performed in citrated frozen platelet poor plasma (PPP). Blood was obtained from 26 MM pts, Salmon and Durie stage II and III, 62.5 years old (42–77), 9 males and 17 females, 10 treated with thalidomide (100–200mg/d orally) and dexamethasone (40mg/d for 4 days) (TD group) and 16 receiving no treatment (MM group). 13 healthy volunteers formed the control group. Thrombin Generation (TG) was initiated by adding the PPP reagent (Thrombogram-Thrombinoscope®) and the triggering solution (CaCl2 and fluorogenic substrate). We analyzed the endogenous thrombin potential (ETP), the Cmax and the velocity index of TG. The plasma levels of sTM in PPP were measured by a specific ELISA (Diagnostica Stago, France). In the MM group we observed an increase of the ETP, though not significant compared to the controls. The Cmax was almost equal to the control group value, while the velocity index of TG was statistically lower in the MM group compared to controls. In the TD group, a statistically significant increase of ETP was observed as compared to the control group. The Cmax was higher, compared to controls, though not significantly, whereas the velocity index of TG was almost equal to the control group value. There was no significant difference in the TG parameters between MM and TD groups. sTM in the control group was 45±14ng/ml. Both groups of pts had significantly increased sTM plasma levels as compared to the control but the difference between the two groups did not reach significance. Results are shown in Table 1. In patients with MM coexists an increase of sTM, a marker of endothelial cell damage, together with an increased TG capacity. The addition of thalidomide treatment is associated with a slight but not significant increase of ETP and Cmax. The co-existence of endothelial cell damage with increased TG capacity could be associated to the increased thrombotic risk in MM patients treated with thalidomide. This hypothesis will be controlled in a prospective study.Table 1:Thrombogram parameters and sTM plasma levels of studied pts.ControlMM groupTD groupETP (nM×min)1399±2971651±4781747±448*Cmax (nM)366±54342±52402±99Velocity Index (nM/min)198±45160±19*184±65STM (ng/ml)45±1484±42*73±30** Results significantly different between the MM and TD groups and the control group (p<0.05 vs the control group)

Changes in Components of the Natural Coagulation Inhibitor System, in Patients with Antiphospholipid Antibodies and/or the Lupus Inhibitor.

The cell surface glycoproteins thrombomodulin (TM) and endothelial protein C receptor (EPCR) are major intermediaries in the down-regulation of thrombin and are noted to be shed from endothelial cells (ECs) due to the actions of proinflammatory cytokines, thrombin and other agents. Antiphospholipid antibodies (APLA) have been described as perturbing ECs. The level of protein S (PS) and protein Z (PZ) have been reported to inconsistently relate to the presence of antibodies and clinical outcomes. We previously reported using a coagulation assay system to demonstrate that adverse pregnancy outcomes (APO) are associated with a greater incidence of resistance to the anticoagulant effects of TM. In the current study we measured the plasma levels of soluble TM (sTM), soluble EPCR (sEPCR) as a possible indicator of APLA-EC interaction. We measured levels of free PS, PZ, sTM and sEPCR in patients (pts) with APLA and/or lupus inhibitor (LI), and correlated the findings with a positive or negative history for thrombosis [THRM(+) or (−)]. APO were not assessed at this time. The study group consisted of 26 males and 60 females, ages ranging from 25 to 90 years; mean of 56. GROUP 1: 33 pts with increased (inc) APLA and 24 of them THRM(+), GROUP 2: 16 pts positive for LI and 7 of them THRM(+), GROUP 3: 37 pts positive for both APLA & LI and 21 of them THRM(+). The pts were compared to 49 normal APLA negative donors (CTR). Pts who have moderate to high levels of anticardiolipin and/or anti-β2 glycoprotein I are APLA positive. LI positive pts have prolonged LI sensitive PTT, and are positive for at least two of the confirmatory tests (Hexagonal phase assay, platelet neutralization procedure, and diluted Russel Viper Venom Time Ratio). GROUP 1 has statistically significant (SS) (p<0.05) decreased (dec) sTM, sEPCR, and free PS when compared to CTR (sTM 1.0+/−1.4 vs 5.1+/−3.3ng/ml, sEPCR 43+/−53 vs 145+/−140ng/ml, free PS 63+/−25 vs 76+/−14%). Free PS is SS lower in the THRM(−) vs. THRM(+). PZ levels do not demonstrate SS differences in the subset comparisons. 8% of THRM(+) pts have PZ deficiency (PZ <1.0ug/ml) with none noted in the THRM(−) pts. Free PS is dec in a majority of the THRM(−). This might be related to the much higher % of females in the THRM(−). Therefore issues such as use of OCP, estrogens, current or recent pregnancy might influence PS. The incidents of dec sTM levels (<2.0ng/ml) are surprisingly higher in this group of patients (82%). This is strikingly higher than the CTR (4%). There is no apparent difference in the THRM(+) to THRM(−). The number of patients with dec sEPCR (<5ng/ml) is much lower however; none of the THRM(−) has dec levels. Inc sTM (>8.0ng/ml) nor inc sEPCR (>284ng/ml) is noted in any of the Pts. In GROUP 2, there is SS dec sTM & sEPCR (sTM 1.6+/−1.8ng/ml, sEPCR 42+/−32ng/ml) vs. CTR with no SS difference in the THRM(+) vs. THRM(−). In GROUP 3, sEPCR is SS dec in pts (sEPCR 68+/−100ng/ml) vs. CTR and CTR vs THRM(+) (sEPCR 29+/−25ng/ml). sTM is SS dec in the CTR vs. THRM(+) (sTM 1.3+/11.4ng/ml). Our data shows low levels of sTM and sEPCR in the APLA patients. This might indicate that the levels are consumed by antibody interactions and could indicate that the APLA and associated other antibodies might interfere with their functions. Previous reports indicating a resistance to TM in a coagulation assay method in patients with THRM and APO raises the possibility of an inhibiting substance present in the APLA. Further work in larger patient groups is necessary to clarify these issues.

W14-P-004 A thrombomodulin haplotype (V/DELTT),associated with risk of coronary heart disease, does not influence plasma levels of soluble thrombomodulin

Neuronal damage after transient cerebral ischemia is exacerbated by signaling pathways involving activated platelet-activating factor (PAF) and ameliorated by PAF-acetylhydrolase (PAF-AH); but whether cerebral neurons can be rescued by human recombinant PAF-AH (rPAF-AH) remains unknown. Adult male mice underwent a 60 min middle cerebral artery occlusion (MCAO) and reperfusion for 24 h. Then, the mice received intravenous tail injections with different drugs. Neurological behavioral function was evaluated by Bederson's test, and cerebral infarction volume was assessed with tetrazolium chloride (TTC) staining. mRNA and protein expression levels of matrix metalloproteinase-2 (MMP-2, collagenase-1), MMP-9 (gelatinase-B), and vascular endothelial growth factor (VEGF) were determined by quantitative real-time PCR (RT-PCR) and western blot analysis, respectively. Compared with the vehicle group, rPAF-AH significantly improved sensorimotor function (42%, P = 0.0001). The volume of non-infarcted brain tissue was increased by the rPAF-AH treatment (16.3 ± 4.6% vs. 46.0 ± 10.3%, respectively). rPAF-AH significantly reduced mRNA and protein levels of MMP-2 and MMP-9, but increased the mRNA (P < 0.001) and protein levels (P < 0.01) of VEGF. These results demonstrate that rPAF-AH provides neuroprotection against ischemic injury. Neuroprotection might be induced not only by decrease in MMP-2 and MMP-9 expression, but also by increased VEGF expression.

The Lectin-like Domain of Thrombomodulin Confers Protection from Neutrophil-mediated Tissue Damage by Suppressing Adhesion Molecule Expression via Nuclear Factor κB and Mitogen-activated Protein Kinase Pathways

Thrombomodulin (TM) is a vascular endothelial cell (EC) receptor that is a cofactor for thrombin-mediated activation of the anticoagulant protein C. The extracellular NH2-terminal domain of TM has homology to C-type lectins that are involved in immune regulation. Using transgenic mice that lack this structure (TMLeD/LeD), we show that the lectin-like domain of TM interferes with polymorphonuclear leukocyte (PMN) adhesion to ECs by intercellular adhesion molecule 1–dependent and –independent pathways through the suppression of extracellular signal–regulated kinase (ERK)1/2 activation. TMLeD/LeD mice have reduced survival after endotoxin exposure, accumulate more PMNs in their lungs, and develop larger infarcts after myocardial ischemia/reperfusion. The recombinant lectin-like domain of TM suppresses PMN adhesion to ECs, diminishes cytokine-induced increase in nuclear factor κB and activation of ERK1/2, and rescues ECs from serum starvation, findings that may explain why plasma levels of soluble TM are inversely correlated with cardiovascular disease. These data suggest that TM has antiinflammatory properties in addition to its role in coagulation and fibrinolysis.

Soluble plasma thrombomodulin levels in patients with chronic myeloproliferative disorder.

The plasma levels of soluble thrombomodulin (TM) were measured in 44 patients with chronic myeloproliferative disorder, 15 with polycythemia vera (PV), 29 with essential thrombocythemia (ET), and a group of 62 matched healthy controls. The younger patients had significantly lower TM levels (mean: 15.6 +/- 4.8 ng/mL) than the older patients (mean: 28.6 +/- 8.2 ng/mL, p < .001). Moreover, a significant negative correlation between platelet counts and plasma TM levels in healthy persons was noted (r = 0.317, p < .05). The only significant difference we found in plasma TM levels between patients and controls or among patients was between the young patients with ET (mean: 29.0 +/- 19.2 ng/mL) and young healthy controls (mean: 15.6 +/- 4.8 ng/mL). It is possible that younger ET patients with more active platelets are more susceptible to earlier vascular damage. The lack of any significant difference compared with the older patient population supports this hypothesis.

RETRACTED: Normothermic versus hypothermic cardiopulmonary bypass: Do changes in coagulation differ?

The differences between hypothermic and normothermic cardiopulmonary bypass (CPB) on platelet function and endothelial-related coagulation (eg, the thrombomodulin/protein C/protein S system) should be investigated. According to a randomized sequence, 30 patients undergoing aortocoronary bypass grafting underwent either hypothermic (rectal temperature, 27 degrees C to 28 degrees C, n = 15) or normothermic CPB (rectal temperature, more than 35 degrees C, n = 15). Arterial blood samples were taken after induction of anesthesia (baseline values), before, during, and immediately after CPB, 5 hours after CPB, and on the morning of the first postoperative day. Circulating thrombomodulin, (free) protein S, protein C, and thrombin/antithrombin III complex were measured from these samples. Platelet function was assessed by aggregometry (turbidometric technique) induced by adenosine diphosphate (2 mumol/L), collagen (4 micrograms/L), and epinephrine (25 mumol/L). Hypothermic patients showed a significantly higher blood loss and need for homologous blood than the normothermic patients. Thrombomodulin plasma level increased more in the hypothermic (from 28 +/- 5 ng/mL to 60 +/- 10 ng/mL) than in the normothermic group (from 28 +/- 7 ng/mL to 41 ng/mL); p < 0.05). Both protein C and (free) protein S were reduced significantly in the hypothermic (protein C, from 88% +/- 25% to 60% +/- 11%; protein S, from 71% +/- 10% to 40% +/- 8%) than in the normothermic patients. Platelet aggregation was significantly more decreased in the hypothermic (adenosine diphosphate, maximum decrease by -43% relative to baseline) than in the normothermic patients (adenosine diphosphate, maximum decrease by -22% relative to baseline). In the hypothermic CPB group, platelet aggregation had recovered incompletely, whereas in the normothermic patients platelet aggregation even slightly exceeded baseline values. Hypothermic CPB resulted in more pronounced alterations of platelet aggregation and endothelial-related coagulation than normothermic CPB. Plasma levels of soluble thrombomodulin were more increased in hypothermic than in normothermic CPB indicating more extensive endothelial damage or activation associated with hypothermic CPB.

Soluble thrombomodulin antigen in plasma is increased in patients with acute myocardial infarction treated with thrombolytic therapy

Thrombomodulin (TM) is an integral endothelial cell membrane protein that functions as a cofactor for thrombin mediated activation of protein C. The anticoagulant functions of the protein C system are important in contributing to a hemostatic balance and prevention of thromboembolic disease. It has been suggested that impaired TM cofactor function could also constitute a prothrombotic abnormality leading to thromboembolic diseases. TM exists not only on the surface of endothelial cells but also as soluble fragment(s) circulating in plasma. The concept of a thrombotic occlusion as the critical event in acute myocardial infarction (AMI) forms the rationale for thrombolytic therapy. After successful reperfusion, patients remain at substantial risk for recurrent infarctions due to rethrombosis. The balance between procoagulant and anticoagulant mechanisms in the postthrombolytic phase have not been studied in detail. We have studied whether the plasma levels of soluble TM are influenced by thrombolytic therapy with streptokinase in patients suffering from AMI. Soluble TM concentrations increased significantly by 24 to 48h after thrombolytic treatment, simultaneously with an increase in C-reactive protein (CRP, a marker of the inflammatory component of the cell damage) and in thio-barbituric acid reactive substances (TBARS, an indirect marker of lipid peroxidation).

Increased plasma levels of soluble thrombomodulin in patients with sepsis and organ failure.

The fact that thrombomodulin (TM) is released into the bloodstream from damaged vascular endothelial cells led us to hypothesize that plasma levels of soluble TM could be an indicator of the development of organ failure. In this study, we examined the changes in plasma levels of TM in 60 septic patients and 13 postsurgical patients, and investigated the circulating levels of interleukin 6 (IL-6) and polymorphonuclear leukocyte elastase (PMN-E) to determine the mechanism causing the excess liberation of TM. The arterial ketone body ratio (AKBR) was also measured as an indicator of the hepatocyte energy state. Of the 60 septic patients, 26 developed organ failure, 10 of whom died. In contrast, none of the postsurgical patients developed organ failure. The mean plasma level of TM was significantly higher in the septic patients who developed organ failure compared to those without organ failure (P < 0.001) or the postsurgical patients (P < 0.001). Furthermore, those patients whose plasma TM values became elevated over 6.0 ng/ml frequently developed complications. A positive correlation was also observed between the plasma TM levels and the IL-6 (P < 0.01) and PMN-E levels (P < 0.01). In contrast, a negative correlation was seen between the plasma TM levels and the AKBR (P < 0.01). These findings show that plasma TM could be a useful indicator of impending organ failure during sepsis.

Elevated serum and urinary thrombomodulin levels in patients with non-insulin-dependent diabetes mellitus

Increased plasma levels of soluble thrombomodulin have been reported in several disorders as a marker for vascular endothelial damage. Serum and urinary thrombomodulin levels were measured in 79 patients with non-insulin-dependent diabetes mellitus. Both levels were significantly higher (23.5 ± 6.1 ng/ml and 146.6 ± 64.9 ng/ml, respectively) than those of normal healthy controls (18.8 ± 3.1 ng/ml, P < 0.001, and 96.8 ± 60.3 ng/ml, P < 0.01). Serum thrombomodulin levels increased in keeping with urinary albumin levels. In urine, thrombomodulin was lower in the macroalbuminuria group than in the microalbuminuria group, suggesting two mechanisms: intravascular overproduction and impaired renal clearance. Both serum and urinary thrombomodulin levels in diabetic patients might be predictors for very early nephropathy.

Plasma levels of soluble thrombomodulin increase in cases of disseminated intravascular coagulation with organ failure.

We examined the changes in plasma levels of soluble thrombomodulin in 66 cases of disseminated intravascular coagulation (DIC), to investigate the damage to vascular endothelial cells and its relationship to multiple organ failure. A significant elevation of plasma levels of soluble thrombomodulin was observed in most cases of DIC, especially in patients with sepsis. However, no such significant elevation was observed in patients with acute promyelocytic leukemia. Plasma levels of both soluble thrombomodulin and active plasminogen activator inhibitor were higher in the cases of DIC with multiple organ failure than in those without multiple organ failure. The levels of soluble thrombomodulin were decreased with the clinical improvement in most cases of DIC but were further increased or remained at high levels in patients who showed no improvement of DIC. It was suggested that an increase in soluble thrombomodulin indicates the damage to the vascular endothelial cells in cases of DIC and that the damage to vascular endothelial cells plays some role in further progression of multiple organ failure.