Kinetics of Thrombin Generation in Patients with Multiple Myeloma.

Abstract 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. Control MM group TD group * Results significantly different between the MM and TD groups and the control group (p<0.05 vs the control group) ETP (nM×min) 1399±297 1651±478 1747±448* Cmax (nM) 366±54 342±52 402±99 Velocity Index (nM/min) 198±45 160±19* 184±65 STM (ng/ml) 45±14 84±42* 73±30*

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Soluble Thrombomodulin Attenuates Endothelial Cell Damage in Hepatic Sinusoidal Obstruction Syndrome

In Vivo ◽

10.21873/invivo.11393 ◽

2018 ◽

Vol 32 (6) ◽

pp. 1409-1417 ◽

Cited By ~ 1

Author(s):

SATOSHI TAKADA ◽

TOMOHARU MIYASHITA ◽

YASUHIKO YAMAMOTO ◽

SHUNSUKE KANOU ◽

SEIICHI MUNESUE ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Damage ◽

Sinusoidal Obstruction Syndrome ◽

Endothelial Cell Damage ◽

Soluble Thrombomodulin ◽

Hepatic Sinusoidal Obstruction Syndrome

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166 Fibrinolysis, thrombin generation and endothelial cell damage in patients with antiphospholipid antibodies

Fibrinolysis and Proteolysis ◽

10.1016/s0268-9499(96)80253-0 ◽

1996 ◽

Vol 10 ◽

pp. 50

Keyword(s):

Endothelial Cell ◽

Antiphospholipid Antibodies ◽

Thrombin Generation ◽

Cell Damage ◽

Endothelial Cell Damage

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Comparison of the Changes in Corneal Endothelial Cells after Pars Plana and Anterior Chamber Ahmed Valve Implant

Journal of Ophthalmology ◽

10.1155/2015/486832 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Ji Won Seo ◽

Jong Yeon Lee ◽

Dong Heun Nam ◽

Dae Yeong Lee

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Anterior Chamber ◽

Cell Damage ◽

Corneal Endothelial Cells ◽

Refractory Glaucoma ◽

Endothelial Cell Damage ◽

Significant Difference ◽

Pars Plana

Purpose. To compare the changes in corneal endothelial cells after pars plana Ahmed glaucoma valve (AGV) implantation with those after the anterior chamber AGV implantation for refractory glaucoma.Methods. The medical records of 18 eyes with pars plana implantation of AGV (ppAGV) were reviewed retrospectively and were compared with 18 eyes with the anterior chamber AGV (acAGV) implant. The preoperative and postoperative endothelial cells, intraocular pressure (IOP), and postoperative complications during the follow-up in both groups were compared.Results. The average follow-up was 18 months. The postoperative endothelial cells in the ppAGV and acAGV groups were 2044 ± 303 and 1904 ± 324, respectively(P=0.25). The average percentage decrease in the endothelial cells in the ppAGV and acAGV groups at 18 months was 12.5% and 18.4%, respectively, and showed significant difference between the 2 groups(P=0.01). No difference in IOP control and the number of postoperative glaucoma medications was observed between the 2 groups.Conclusions. Endothelial cell damage in the ppAGV group for refractory glaucoma appeared to be lower than that in the acAGV group. Therefore, pars plana implantation of AGV may be preferred as it may have lower level of endothelial cell damage while maintaining similar level of IOP control.

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Soluble Adhesion Molecules and Endothelial Cell Damage in HIV Infected Patients

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656027 ◽

1997 ◽

Vol 77 (04) ◽

pp. 646-649 ◽

Cited By ~ 60

Author(s):

Martine Seigneur ◽

Joël Constans ◽

Andrew Blann ◽

Martine Renard ◽

Jean Luc Pellegrin ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Count ◽

Cell Damage ◽

Severe Disease ◽

Endothelial Damage ◽

Endothelial Cell Damage ◽

Soluble Adhesion Molecules ◽

Cd4 Cell Count ◽

Soluble Thrombomodulin ◽

Cd4 Cell

SummaryEndothelial damage is present in HIV infection but our understanding of markers and mechanisms is incomplete. We found increased levels of markers of endothelial cell damage such as von Willebrand factor (vWf), soluble thrombomodulin (sTM) and adhesion molecule E- selectin in 90 subjects seropositive for HIV relative to healthy controls. sTM was strongly raised in those patients with the lowest CD4+ cell count (p <0.001), but levels of vWf increased at each incremental fall in CD4+ cell count and the two indices correlated significantly (r = -0.485, p <0.001). vWf correlated strongly with levels of the inflammatory cytokines tumor necrosis factor (TNF-α) and alpha interferon (IFN-α) but sTM correlated only weakly with IFN-α. We suggest that increased vWf is largely the result of inflammatory stimulus of the endothelium but that sTM is found only in those patients with more severe disease, and so truely represents endothelial damage.

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Einfluß von Ramipril auf den Verlauf des Plasma-Thrombomodulinspiegels bei Diabetikern

VASA ◽

10.1024/0301-1526.28.3.172 ◽

1999 ◽

Vol 28 (3) ◽

pp. 172-180 ◽

Cited By ~ 16

Author(s):

Borcea ◽

Morcos ◽

Isermann ◽

Henkels ◽

Ziegler ◽

...

Keyword(s):

Blood Pressure ◽

Endothelial Cell ◽

Enzyme Inhibitor ◽

Cell Damage ◽

Treated Group ◽

Control Group ◽

Diabetic Patients ◽

Albumin Concentration ◽

Double Blind Study ◽

Endothelial Cell Damage

Background: In diabetic patients endothelial dysfunction is reflected by an increased urinary albumine excretion, which can be reduced by ACE-inhibitors. No data are available showing a endothelial-protective effect by determining a marker reflecting endothelial cell-damage. Patients and methods: The effect of angiotensin converting enzyme inhibitor (ACEI) (ramipril) treatment on the progression of endothelial cell damage, – assessed by measurement of plasma-thrombomodulin (TM), – was investigated in an open, non randomized, prospective pilot study over a period of 18 months in diabetic patients. 87 patients with an urinary albumin concentration (UAC) below 100 mg/l at baseline were included. 46 patients were treated without ACEI and served as a control group, 41 patients were treated with ACEI. Participation in this study did not affect intensity in the treatment of blood glucose, blood pressure or diet. At study entry both groups were comparable with respect to duration of diabetes, diabetic complications, vascular risk factors, body mass index, medications used to treat diabetes, presence of hypertension, glycemic control, tryglycerides, HDL cholesterol, creatinine, UAC and plasma-TM. Age, blood pressure, and total cholesterol were significantly higher in the ACEI group, compared with the control group. Results: After a follow up of 18 months a significant increase in UAC (DeltaUAC = 10.48 mg/l, p = 0.03) and plasma-TM (DeltaTM = 3.06 ng/l, p = 0.009) was observed in the control group, while in the ACEI treated group a decrease in albuminuria (DeltaUAC = –7.44 mg/l, p = 0.01) and plasma-TM (DeltaTM = –4.78 ng/l, p = 0.001) was seen. Despite a similar approach in hypertension and diabetes control in both groups, UAC and plasma-TM decreased after 18 months only in the ACEI treated group. Treatment with ACEI was the strongest predictor (p=0.0001) indicating decrease of UAC and plasma-TM (multi regression analysis). Conclusion: Plasma-thrombomodulin might be a useful marker for assessing the efficacy of drugs potentially protecting the vessel wall. While the present study was a open, non randomized study, further investigation is necessary to proof the hypothesis in a randomized, placebo-controlled, double-blind study.

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Sa1556 Cytoprotective Effect of Soluble Thrombomodulin Attenuates Endothelial Cell Damage in Sinusoidal Obstruction Syndrome

Gastroenterology ◽

10.1016/s0016-5085(16)33599-5 ◽

2016 ◽

Vol 150 (4) ◽

pp. S1066

Author(s):

Satoshi Takada ◽

Tomoharu Miyashita ◽

Makoto Nakura ◽

Shunsuke Kanou ◽

Seiichi Munesue ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Damage ◽

Sinusoidal Obstruction Syndrome ◽

Cytoprotective Effect ◽

Endothelial Cell Damage ◽

Soluble Thrombomodulin

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Plasma Levels of Lipoprotein(a) Are Elevated in Patients with the Antiphospholipid Antibody Syndrome

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642454 ◽

1994 ◽

Vol 71 (04) ◽

pp. 424-427 ◽

Cited By ~ 42

Author(s):

Masahide Yamazaki ◽

Hidesaku Asakura ◽

Hiroshi Jokaji ◽

Masanori Saito ◽

Chika Uotani ◽

...

Keyword(s):

Plasma Levels ◽

Active Form ◽

Plasminogen Activator Inhibitor ◽

Arterial System ◽

Control Group ◽

Antiphospholipid Antibody ◽

Antiphospholipid Antibody Syndrome ◽

Lipoprotein A ◽

Soluble Thrombomodulin ◽

Relationship Of

SummaryThe mechanisms underlying clinical abnormalities associated with the antiphospholipid antibody syndrome (APAS) have not been elucidated. We measured plasma levels of lipoprotein(a) [Lp(a)], the active form of plasminogen activator inhibitor (active PAI), thrombin-antithrombin III complex (TAT) and soluble thrombomodulin (TM), to investigate the relationship of these factors to thrombotic events in APAS. Mean plasma levels of Lp(a), TAT, active PAI and TM were all significantly higher in patients with aPL than in a control group of subjects. Plasma levels of Lp(a) and active PAI were significantly higher in patients with aPL and arterial thromboses than in patients with aPL but only venous thromboses. There was a significant correlation between plasma levels of Lp(a) and active PAI in patients with aPL. These findings suggest that patients with aPL are in hypercoagulable state. High levels of Lp(a) in plasma may impair the fibrinolytic system resulting in thromboses, especially in the arterial system.

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Levels of Prothrombin Fragment F1+2 in Patients with Hyperhomocysteinemia and a History of Venous Thromboembolism

Thrombosis and Haemostasis ◽

10.1055/s-0038-1665405 ◽

1997 ◽

Vol 78 (05) ◽

pp. 1327-1331 ◽

Cited By ~ 21

Author(s):

Paul A Kyrle ◽

Andreas Stümpflen ◽

Mirko Hirschl ◽

Christine Bialonczyk ◽

Kurt Herkner ◽

...

Keyword(s):

Venous Thromboembolism ◽

Thrombin Generation ◽

Oral Anticoagulant Therapy ◽

Oral Anticoagulants ◽

Control Group ◽

Prothrombin Fragment ◽

Hemostatic System ◽

Significant Difference ◽

System Activation ◽

One Year

SummaryIncreased thrombin generation occurs in many individuals with inherited defects in the antithrombin or protein C anticoagulant pathways and is also seen in patients with thrombosis without a defined clotting abnormality. Hyperhomocysteinemia (H-HC) is an important risk factor of venous thromboembolism (VTE). We prospectively followed 48 patients with H-HC (median age 62 years, range 26-83; 18 males) and 183 patients (median age 50 years, range 18-85; 83 males) without H-HC for a period of up to one year. Prothrombin fragment Fl+2 (Fl+2) was determined in the patient’s plasma as a measure of thrombin generation during and at several time points after discontinuation of secondary thromboprophylaxis with oral anticoagulants. While on anticoagulants, patients with H-HC had significantly higher Fl+2 levels than patients without H-HC (mean 0.52 ± 0.49 nmol/1, median 0.4, range 0.2-2.8, versus 0.36 ± 0.2 nmol/1, median 0.3, range 0.1-2.1; p = 0.02). Three weeks and 3,6,9 and 12 months after discontinuation of oral anticoagulants, up to 20% of the patients with H-HC and 5 to 6% without H-HC had higher Fl+2 levels than a corresponding age- and sex-matched control group. 16% of the patients with H-HC and 4% of the patients without H-HC had either Fl+2 levels above the upper limit of normal controls at least at 2 occasions or (an) elevated Fl+2 level(s) followed by recurrent VTE. No statistical significant difference in the Fl+2 levels was seen between patients with and without H-HC. We conclude that a permanent hemostatic system activation is detectable in a proportion of patients with H-HC after discontinuation of oral anticoagulant therapy following VTE. Furthermore, secondary thromboprophylaxis with conventional doses of oral anticoagulants may not be sufficient to suppress hemostatic system activation in patients with H-HC.

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