Soluble thrombomodulin ameliorates aberrant hemostasis after rewarming in a rat accidental hypothermia model

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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The Glycosaminoglycan of Recombinant Human Soluble Thrombomodulin Affects Antithrombotic Activity in a Rat Model of Tissue Factor-Induced Disseminated Intravascular Coagulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648448 ◽

1992 ◽

Vol 67 (03) ◽

pp. 366-370 ◽

Cited By ~ 16

Author(s):

Katsuhiko Nawa ◽

Teru Itani ◽

Mayumi Ono ◽

Katsu-ichi Sakano ◽

Yasumasa Marumoto ◽

...

Keyword(s):

Tissue Factor ◽

Disseminated Intravascular Coagulation ◽

Rat Model ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Soluble Thrombomodulin ◽

Intravascular Coagulation ◽

Platelet Counts ◽

Recombinant Human Soluble Thrombomodulin

SummaryPrevious studies on recombinant human soluble thrombomodulin (rsTM) from Chinese hamster ovary cells revealed that rsTM was expressed as two proteins that differed functionally in vitro due to the presence (rsTMp) or absence (rsTMa) of chondroitin-4-sulfate. The current study evaluates the in vivo behavior of rsTM in rats and in a rat model of tissue factor-induced disseminated intravascular coagulation (DIC). rsTMp was more potent than rsTMa for prolongation of the activated partial thromboplastin time (APTT) and their in vivo half-lives determined by ELISA were 20 min for rsTMp and 5.0 h for rsTMa. Injection of a tissue factor suspension (5 mg/kg) resulted in DIC as judged by decreased platelet counts and fibrinogen concentrations, prolonged APTT, and increased fibrin and fibrinogen degradation products (FDP) levels. A bolus injection of either rsTM (0.2 mg/kg) 1 min before induction of DIC essentially neutralized effects on platelets, fibrinogen, and FDP levels, and had only a moderate effect on APTT prolongation. The dose of anticoagulant to inhibit the drop in platelet counts by 50% (ED50) was 0.2 mg/kg rsTMa, 0.07 mg/kg rsTMp, and 7 U/ kg heparin. The effect of increasing concentrations of rsTM and heparin on bleeding times were compared in experiments involving incision of the rat tail. Doubling of the bleeding times occurred at 5 mg/kg rsTMa, 3 mg/kg rsTMp or 90 U/kg heparin. These values represent a 25-fold increase over the ED50 for rsTMa, 43-fold for rsTMp and 13-fold for heparin. These results suggest that rsTMp is a potent anticoagulant to inhibit the platelet reduction when injected prior to the induction of DIC in rats.

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Recombinant Human Soluble Thrombomodulin Delivers Bounded Thrombin to Antithrombin III: Thrombomodulin Associates with Free Thrombin and Is Recycled to Activate Protein C

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649597 ◽

1993 ◽

Vol 70 (03) ◽

pp. 418-422 ◽

Cited By ~ 23

Author(s):

Masaharu Aritomi ◽

Naoko Watanabe ◽

Rika Ohishi ◽

Komakazu Gomi ◽

Takao Kiyota ◽

...

Keyword(s):

Protein C ◽

Antithrombin Iii ◽

Transmembrane Domain ◽

Chinese Hamster Ovary Cells ◽

Time Lag ◽

Chinese Hamster ◽

Ovary Cells ◽

Soluble Thrombomodulin ◽

Simulation Based ◽

Recombinant Human Soluble Thrombomodulin

SummaryRecombinant human soluble thrombomodulin (rhs-TM), having no transmembrane domain or chondroitin sulfate, was expressed in Chinese hamster ovary cells. Interactions between rhs-TM, thrombin (Th), protein C (PC) and antithrombin III (ATIII) were studied. Equilibrium between rhs-TM and Th had no detectable time lag in clotting inhibition (K d = 26 nM) or PC activation (K d = 22 nM), while ATIII inhibited Th at a bimolecular rate constant = 5,200 M-1s-1 (K d <0.2 nM). A mixture of ATIII, Th and rhs-TM showed that ATIII reacted with Th slower than rhs-TM, whose presence did not affect the reaction between ATIII and Th. In a mixture of rhs-TM, ATIII and PC, the repeated addition of Th caused the repeated activation of PC; which was consistent with the Simulation based on the assumption that rhs-TM is recycled as a Th cofactor. From these results, we concluded that upon inhibition of the rhs-TM-Th complex by ATIII, rhs-TM is released to recombine with free Th and begins to activate PC, while the Th-ATIII complex does not affect rhs-TM-Th equilibrium.

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Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653872 ◽

1995 ◽

Vol 73 (05) ◽

pp. 805-811 ◽

Cited By ~ 12

Author(s):

Yasuo Takahashi ◽

Yoshitaka Hosaka ◽

Hiromi Niina ◽

Katsuaki Nagasawa ◽

Masaaki Naotsuka ◽

...

Keyword(s):

Human Urine ◽

Specific Activity ◽

Anticoagulant Activity ◽

Rabbit Lung ◽

Soluble Thrombomodulin ◽

Molecular Weights ◽

Dose Dependent Fashion ◽

Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

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Clinical staging of accidental hypothermia: the Revised Swiss System

Resuscitation ◽

10.1016/j.resuscitation.2021.02.038 ◽

2021 ◽

Author(s):

Martin E. Musi ◽

Alison Sheets ◽

Ken Zafren ◽

Hermann Brugger ◽

Peter Paal ◽

...

Keyword(s):

Clinical Staging ◽

Accidental Hypothermia

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Thrombomodulin is upregulated in the kidneys of women with pre-eclampsia

Scientific Reports ◽

10.1038/s41598-021-85040-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Cleo C. L. van Aanhold ◽

Manon Bos ◽

Katrina M. Mirabito Colafella ◽

Marie-Louise P. van der Hoorn ◽

Ron Wolterbeek ◽

...

Keyword(s):

Glomerular Filtration ◽

Early Stage ◽

Vascular Inflammation ◽

Angiogenesis Inhibitor ◽

Serum Levels ◽

Dependent Manner ◽

Glomerular Filtration Barrier ◽

Soluble Thrombomodulin ◽

Filtration Barrier ◽

Glomerular Endothelium

AbstractThe endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ETAR blockade, but not dual ETA/BR blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.

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Admission biomarkers among patients with acute myocardial-infarction related cardiogenic shock with or without out-of-hospital cardiac arrest

European Heart Journal Acute Cardiovascular Care ◽

10.1093/ehjacc/zuab020.090 ◽

2021 ◽

Vol 10 (Supplement_1) ◽

Author(s):

M Thoegersen ◽

M Frydland ◽

O Helgestad ◽

LO Jensen ◽

J Josiassen ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Cardiac Arrest ◽

Coronary Angiography ◽

Cardiogenic Shock ◽

Plasma Concentrations ◽

Endothelial Damage ◽

Soluble Thrombomodulin ◽

Catheterization Laboratory ◽

Hospital Cardiac Arrest

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Lundbeck Foundation OnBehalf Critical Cardiac Care Research Group Background Approximately half of all patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) present with out-of-hospital cardiac arrest (OHCA). Cardiogenic shock due to OHCA is caused by abrupt cessation of circulation, whereas AMICS without OHCA is due to cardiac failure with low cardiac output. Thus, there may also be differences between the two conditions in terms of blood borne biomarkers. Purpose To explore the potential differences in the admission plasma concentrations of biomarkers reflecting tissue perfusion (lactate), neuroendocrine response (mid-regional proadrenomedullin [MRproADM], Copeptin, pro-atrial natriuretic peptide [proANP]), endothelial damage (Syndecan-1, soluble thrombomodulin [sTM]), inflammation (soluble suppression of tumorigenicity 2 [sST2]) and kidney injury (neutrophil gelatinase-associated lipocalin [NGAL]), in patients with AMICS presenting with or without OHCA. Method Consecutive patients admitted for acute coronary angiography due to suspected ST-elevation myocardial infarction (STEMI) were enrolled during a 1-year period. A total of 2,713 patients were screened. In the present study 86 patients with confirmed STEMI and CS at admission were included. Results Patients with OHCA (had significantly higher median admission concentrations of Lactate (6,9 mmol/L vs. 3.4 mmol/L p <0.001), NGAL (220 ng/ml vs 150 ng/ml p = 0.046), sTM (10 ng/ml vs. 8.0 ng/ml p = 0.026) and Syndecan-1 (160 ng/ml vs. 120 ng/ml p= 0.015) and significantly lower concentrations of MR-proADM (0.85 nmol/L vs. 1.6 nmol/L p <0.001) and sST2 (39 ng/ml vs. 62 ng/ml p < 0.001). After adjusting for age, sex, and time from symptom onset to coronary angiography, lactate (p = 0.008), NGAL (p = 0.03) and sTM (p = 0.011) were still significantly higher in patients presenting with OHCA while sST2 was still significantly lower (p = 0.029). There was very little difference in 30-day mortality between the OHCA and non-OHCA groups (OHCA 37% vs. non-OHCA 38%). Conclusion Patients with STEMI and CS at admission with or without concomitant OHCA had similar 30-day mortality but differed in terms of Lactate, NGAL, sTM and sST2 levels at the time of admission to catheterization laboratory. These findings propose that non-OHCA and OHCA patients with CS could be considered as two individual clinical entities. Abstract Figure. Level of biomarkers OHCA vs. non-OHCA

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Unrecognized platelet physiology is the cause of rewarming deaths in accidental hypothermia and neonatal cold injury

Medical Hypotheses ◽

10.1016/j.mehy.2021.110503 ◽

2021 ◽

Vol 148 ◽

pp. 110503

Author(s):

Ian J. Cohen

Keyword(s):

Cold Injury ◽

Accidental Hypothermia ◽

Platelet Physiology

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ABO blood types and sepsis mortality

Annals of Intensive Care ◽

10.1186/s13613-021-00844-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Theis S. Itenov ◽

Daniel I. Sessler ◽

Ashish K. Khanna ◽

Sisse R. Ostrowski ◽

Pär I. Johansson ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Meta Analysis ◽

The United States ◽

Endothelial Damage ◽

Blood Type ◽

Type B ◽

Blood Concentrations ◽

Soluble Thrombomodulin ◽

Blood Types

Abstract Background We aimed to determine if the ABO blood types carry different risks of 30-day mortality, acute kidney injury (AKI), and endothelial damage in critically ill patients with sepsis. This was a retrospective cohort study of three independent cohorts of critically ill patients from the United States and Scandinavia consisting of adults with septic shock. We compared the 30-day mortality across the blood types within each cohort and pooled the results in a meta-analysis. We also estimated the incidence of AKI and degree of endothelial damage, as measured by blood concentrations of soluble thrombomodulin and syndecan-1. Results We included 12,342 patients with severe sepsis. In a pooled analysis blood type B carried a slightly lower risk of 30-day all-cause mortality compared to non-blood type B (adjusted HR 0.88; 95%-CI 0.79–0.98; p = 0.02). There was no difference in the risk of AKI. Soluble thrombomodulin and syndecan-1 concentrations were lower in patients with blood type B and O compared to blood type A, suggesting less endothelial damage. Conclusion Septic patients with blood type B had less endothelial damage, and a small reduction in mortality. The exposure is, however, unmodifiable.

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