Zinc Alters Fibrin Ultrastructure

1987 ◽  
Vol 57 (01) ◽  
pp. 073-076 ◽  
Author(s):  
Gerard Marx ◽  
Pierre Hopmeier ◽  
Dorit Gurfel
Keyword(s):  
Cross Section ◽  
Electron Micrographs ◽  
Fibre Diameter ◽  
Fold Increase ◽  
Fibrin Clot ◽  
Dependent Manner ◽  
Clotting Time ◽  
Concentration Dependent Manner ◽  
Sem Micrographs ◽  
Fibrin Monomer

SummaryTurbidimetric studies indicate that Zn(II) accelerates fibrin gelation [decreases clotting time (CT)] and increases maximal fibrin clot turbidity. For any given level of fibrinogen (0.2-2.6 mg/ ml), the relative fibrin turbidity of thrombin-induced clots increases with Zn(II) in a concentration dependent manner. Zinc-associated turbidity increases are also observed in the presence of 2 mM Ca(II). With citrate, similar turbidity increases are observed, though at higher cation levels. Thus, turbidimetry indicates that the gel formed with Zn(II) is coarser, or has thicker fibre strands. SEM micrographs confirm that fibre thickness ranges from 260 Å to 2600 Å, when Zn(II) levels range from 0-50 uM. With citrate, TEM micrographs reveal amore than 20 x fold increase in fibre diameter (100 Å->2000 Å) with higher Zn(II) (<1 mM) levels. Based on a fibrin monomer cross-section of ~60 Å, the electron micrographs indicate that depending on the Zn(II) levels, fibrin strands are composed of between 2 to 40 monomeric fibrin molecules. Thus, at physiologically relevant levels, Zn(II) can drastically modulate fibrin ultrastructure.

scholarly journals Quercetin Is a Flavonoid Breast Cancer Resistance Protein Inhibitor with an Impact on the Oral Pharmacokinetics of Sulfasalazine in Rats

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 397
Author(s):  
Yoo-Kyung Song ◽  
Jin-Ha Yoon ◽  
Jong Kyu Woo ◽  
Ju-Hee Kang ◽  
Kyeong-Ryoon Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Resistance Protein ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
Concentration Dependent Manner ◽  
Resistance Protein

The potential inhibitory effect of quercetin, a major plant flavonol, on breast cancer resistance protein (BCRP) activity was investigated in this study. The presence of quercetin significantly increased the cellular accumulation and associated cytotoxicity of the BCRP substrate mitoxantrone in human cervical cancer cells (HeLa cells) in a concentration-dependent manner. The transcellular efflux of prazosin, a stereotypical BCRP substrate, was also significantly reduced in the presence of quercetin in a bidirectional transport assay using human BCRP-overexpressing cells; further kinetic analysis revealed IC50 and Ki values of 4.22 and 3.91 μM, respectively. Moreover, pretreatment with 10 mg/kg quercetin in rats led to a 1.8-fold and 1.5-fold increase in the AUC8h (i.e., 44.5 ± 11.8 min∙μg/mL vs. 25.7 ± 9.98 min∙μg/mL, p < 0.05) and Cmax (i.e., 179 ± 23.0 ng/mL vs. 122 ± 23.2 ng/mL, p < 0.05) of orally administered sulfasalazine, respectively. Collectively, these results provide evidence that quercetin acts as an in vivo as well as in vitro inhibitor of BCRP. Considering the high dietary intake of quercetin as well as its consumption as a dietary supplement, issuing a caution regarding its food–drug interactions should be considered.

L-Lysine: A Modulator for the Relative Activity of High Molecular Weight (HMW) and Low Molecular Weight(LHW) Urokinase(UK)

1979 ◽  
Author(s):  
L.L. Shen ◽  
W.H. Holleman
Keyword(s):  
Molecular Weight ◽  
Caproic Acid ◽  
Fibrin Clot ◽  
Relative Activity ◽  
Test Tube ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Plasma Clot ◽  
Concentration Dependent Manner ◽  
The Difference

L-Lysine(Lys), in a concentration dependent manner, progressively inhibited UK-activated lysis of human plasma clots as demonstrated by Ploug test-tube method and elastometric measurements. Lys was more effective with HMW UK than LMW UK, and the effect of Lys with LMW UK from tissue culture and urine sources was the same. Epsilon amino caproic acid(EACA) and tranexamic acid(TXA) were stronger inhibitors but inhibited HMW and LMW UK-induced lysis to the same degree. Elastometric measurements showed that Lys inhibition was not due to its interference with the initial clotting process nor to the reduction of clot rigidity. Amidolytic assays using chromogenic substrates showed that Lys had no direct effect, on UK, and that Lys enhanced the activation of the native Glu-plasminogen(Pg) by LMW UK, but not the activation by HMW UK. When the substrate was human fibrin clots, Lys enhanced the lysis induced by LMW UK while the lysis induced by HMW UK was inhibited; however, the extent of enhancement and inhibition was limited. We concluded that the mode of Lys action is not identical to that of EACA or TXA, and that the stronger Lys inhibition of plasma clot lysis as compared to fibrin clot lysis is due to the potentiation of plasma fibrinolytic inhibitors by Lys. The difference In effect of Lys on HMW and LMW UK-induced lyels is likely due to a partial conformation change of Glu-Pg molecule upon Lys binding. The relatively moderate interaction of Lys with Glu-Fg results In a mildly modified UK substrate which reacts preferentially with the enzyme smaller in size.

scholarly journals Calcitonin Induces IL-6 Production via Both PKA and PKC Pathways in the Pituitary Folliculo-Stellate Cell Line

Endocrinology ◽  
2001 ◽  
Vol 142 (8) ◽  
pp. 3563-3569 ◽  
Author(s):  
Yoshimitsu Kiriyama ◽  
Hiroyuki Tsuchiya ◽  
Takeshi Murakami ◽  
Kumi Satoh ◽  
Yukiko Tokumitsu
Keyword(s):  
Cell Line ◽  
Stellate Cell ◽  
Fold Increase ◽  
Receptor Subtype ◽  
Dependent Manner ◽  
Calcitonin Receptor ◽  
Rt Pcr ◽  
Concentration Dependent Manner ◽  
Mouse Pituitary ◽  
Inhibitor Treatment

Abstract It has been demonstrated that calcitonin-binding sites are present in a variety of tissue types, including in the pituitary gland. Interleukin-6 (IL-6) is also produced in the pituitary and it regulates the secretion of various hormones. In this study, we examined the expression of the calcitonin receptor and the mechanism of IL-6 production induced by calcitonin in the pituitary folliculo-stellate cell line (TtT/GF). The mRNA of calcitonin receptor subtype C1a, but not that of C1b, was detected by RT-PCR in TtT/GF cells and in the normal mouse pituitary. Calcitonin increased cAMP accumulation and IL-6 production in a concentration-dependent manner in TtT/GF cells. As calcitonin activates the PKA and PKC pathways, we investigated the contributions of PKA and PKC to IL-6 production. IL-6 production was only slightly increased by either 8-bromo-cAMP (1 mm) or phorbol 12-myristate 13-acetate (100 nm) alone. However, IL-6 was synergistically induced in the presence of both 8-bromo-cAMP (1 mm) and phorbol 12myristate 13-acetate (100 nm). Furthermore, calcitonin-induced IL-6 production was completely suppressed by H-89 (PKA inhibitor) or GF109203X (PKC inhibitor), indicating that the activation of both PKA and PKC is necessary for calcitonin-induced IL-6 production. On the other hand, pertussis toxin (Gi/Go signaling inhibitor) treatment achieved an approximately 9-fold increase in calcitonin-induced IL-6 production. These results show that calcitonin-stimulated IL-6 production is mediated via both PKA- and PKC-signaling pathways, whereas calcitonin also suppresses IL-6 production by activating Gi/Go proteins in folliculo-stellate cells.

scholarly journals Angiotensin II-Induced Mitogen-Activated Protein Kinase Phosphatase-1 Expression in Bovine Adrenal Glomerulosa Cells: Implications in Mineralocorticoid Biosynthesis

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5573-5581 ◽  
Author(s):  
Andrés J. Casal ◽  
Stéphane Ryser ◽  
Alessandro M. Capponi ◽  
Carine F. Wang-Buholzer
Keyword(s):  
Angiotensin Ii ◽  
Mapk Pathway ◽  
Fold Increase ◽  
Zona Glomerulosa ◽  
Mitogen Activated Protein Kinase ◽  
Receptor Subtype ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Aldosterone Production ◽  
Glomerulosa Cells

Angiotensin II (AngII) stimulates aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex. AngII also triggers the MAPK pathways (ERK1/2 and p38). Because ERK1/2 phosphorylation is a transient process, phosphatases could play a crucial role in the acute steroidogenic response. Here we show that the dual specificity (threonine/tyrosine) MAPK phosphatase-1 (MKP-1) is present in bovine adrenal glomerulosa cells in primary culture and that AngII markedly increases its expression in a time- and concentration-dependent manner (IC50 = 1 nm), a maximum of 548 ± 10% of controls being reached with 10 nm AngII after 3 h (n = 3, P &lt; 0.01). This effect is completely abolished by losartan, a blocker of the AT1 receptor subtype. Moreover, this AngII-induced MKP-1 expression is reduced to 250 ± 35% of controls (n = 3, P &lt; 0.01) in the presence of U0126, an inhibitor of ERK1/2 phosphorylation, suggesting an involvement of the ERK1/2 MAPK pathway in MKP-1 induction. Indeed, shortly after AngII-induced phosphorylation of ERK1/2 (220% of controls at 30 min), MKP-1 protein expression starts to increase. This increase is associated with a reduction in ERK1/2 phosphorylation, which returns to control values after 3 h of AngII challenge. Enhanced MKP-1 expression is essentially due to a stabilization of MKP-1 mRNA. AngII treatment leads to a 53-fold increase in phosphorylated MKP-1 levels and a doubling of MKP-1 phosphatase activity. Overexpression of MKP-1 results in decreased phosphorylation of ERK1/2 and aldosterone production in response to AngII stimulation. These results strongly suggest that MKP-1 is the specific phosphatase induced by AngII and involved in the negative feedback mechanism ensuring adequate ERK1/2-mediated aldosterone production in response to the hormone.

Fibronectin provides a conduit for fibroblast transmigration from collagenous stroma into fibrin clot provisional matrix

1997 ◽  
Vol 110 (7) ◽  
pp. 861-870 ◽  
Author(s):  
D. Greiling ◽  
R.A. Clark
Keyword(s):  
Wound Healing ◽  
In Vitro Model ◽  
Collagen Gel ◽  
Fibrin Clot ◽  
Dependent Manner ◽  
Fibrin Gel ◽  
Concentration Dependent Manner ◽  
Vitro Model ◽  
Early Wound

After injury, the wound space is filled with a fibrin/fibronectin clot containing growth factors released by platelets and monocytes. In response to these factors, fibroblasts migrate into the fibrin clot and contribute to the formation of granulation tissue. The functional mechanisms allowing fibroblasts to leave the collagenous matrix of normal connective tissue and invade the provisional matrix of the fibrin clot have not been fully defined. To investigate these mechanisms we established a new in vitro model which simulates specific aspects of early wound healing, that is, the migration of fibroblasts from a three-dimensional collagen matrix into a fibrin clot. This transmigration could be induced by physiological concentrations of platelet releasate or platelet-derived growth factor BB (PDGF-BB) in a concentration-dependent manner. At 24 hours irradiated fibroblasts invaded the fibrin gel almost as well as non-irradiated cells, indicating that transmigration was independent of proliferation. Plasminogen and its activators appear to be necessary for invasion of the fibrin clot since protease inhibitors decreased the amount of migration. These serine proteases, however, were not necessary for exit from the collagen gel as fibroblasts migrated out of the collagen gel onto a surface coated with fibrin fibrils even in the presence of inhibitors. Removal of fibronectin (FN) from either the collagen gel or the fibrin gel markedly decreased the number of migrating cells, suggesting that FN provides a conduit for transmigration. Cell movement in the in vitro model was inhibited by RGD peptide, and by monoclonal antibodies against the subunits of the alpha5 beta1 and alpha v beta3 integrin receptor. Thus, the functional requirements for fibroblast transmigration from collagen-rich to fibrin-rich matrices, such as occurs in early wound healing, have been partially defined using an in vitro paradigm of this important biologic process.

cADP-ribose activates reconstituted ryanodine receptors from coronary arterial smooth muscle

2001 ◽  
Vol 280 (1) ◽  
pp. H208-H215 ◽  
Author(s):  
Pin-Lan Li ◽  
Wang-Xian Tang ◽  
Hector H. Valdivia ◽  
Ai-Ping Zou ◽  
William B. Campbell
Keyword(s):  
Smooth Muscle ◽  
Lipid Bilayers ◽  
Ryanodine Receptors ◽  
Fold Increase ◽  
Ruthenium Red ◽  
Dependent Manner ◽  
High Concentration ◽  
Open Probability ◽  
Arterial Smooth Muscle ◽  
Concentration Dependent Manner

The present study was designed to test the hypothesis that cADP-ribose (cADPR) increases Ca2+release through activation of ryanodine receptors (RYR) on the sarcoplasmic reticulum (SR) in coronary arterial smooth muscle cells (CASMCs). We reconstituted RYR from the SR of CASMCs into planar lipid bilayers and examined the effect of cADPR on the activity of these Ca2+ release channels. In a symmetrical cesium methanesulfonate configuration, a 245 pS Cs+ current was recorded. This current was characterized by the formation of a subconductance and increase in the open probability (NPo) of the channels in the presence of ryanodine (0.01–1 μM) and imperatoxin A (100 nM). A high concentration of ryanodine (50 μM) and ruthenium red (40–80 μM) substantially inhibited the activity of RYR/Ca2+ release channels. Caffeine (0.5–5 mM) markedly increased the NPo of these Ca2+release channels of the SR, but d- myo-inositol 1,4,5-trisphospate and heparin were without effect. Cyclic ADPR significantly increased the NPo of these Ca2+release channels of SR in a concentration-dependent manner. Addition of cADPR (0.01 μM) into the cis bath solution produced a 2.9-fold increase in the NPo of these RYR/Ca2+release channels. An eightfold increase in the NPo of the RYR/Ca2+ release channels (0.0056 ± 0.001 vs. 0.048 ± 0.017) was observed at a concentration of cADPR of 1 μM. The effect of cADPR was completely abolished by ryanodine (50 μM). In the presence of cADPR, Ca2+-induced activation of these channels was markedly enhanced. These results provide evidence that cADPR activates RYR/Ca2+ release channels on the SR of CASMCs. It is concluded that cADPR stimulates Ca2+ release through the activation of RYRs on the SR of these smooth mucle cells.

scholarly journals Insulin stimulates Mg2+ uptake in mouse distal convoluted tubule cells

1999 ◽  
Vol 277 (6) ◽  
pp. F907-F913 ◽  
Author(s):  
Long-Jun Dai ◽  
Gordon Ritchie ◽  
Brian W. Bapty ◽  
Dirk Kerstan ◽  
Gary A. Quamme
Keyword(s):  
Kinase Inhibitor ◽  
Insulin Receptors ◽  
Distal Tubule ◽  
Fold Increase ◽  
Distal Convoluted Tubule ◽  
Maximal Response ◽  
Thick Ascending Limb ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Camp Formation

Insulin has been shown to be a magnesium-conserving hormone acting, in part, through stimulation of magnesium absorption within the thick ascending limb. Although the distal convoluted tubule possesses the most insulin receptors, it is unclear what, if any, actions insulin has in the distal tubule. The effects of insulin were studied on immortalized mouse distal convoluted tubule (MDCT) cells by measuring cellular cAMP formation with radioimmunoassays and Mg2+ uptake with fluorescence techniques using mag-fura 2. To assess Mg2+ uptake, MDCT cells were first Mg2+ depleted to 0.22 ± 0.01 mM by culturing in Mg2+-free media for 16 h and then placed in 1.5 mM MgCl2, and the changes in intracellular Mg2+ concentration ([Mg2+]i) were measured with microfluorescence. [Mg2+]i returned to basal levels, 0.53 ± 0.02 mM, with a mean refill rate, d([Mg2+]i)/d t, of 164 ± 5 nM/s. Insulin stimulated Mg2+ entry in a concentration-dependent manner with maximal response of 214 ± 12 nM/s, which represented a 30 ± 5% increase in the mean uptake rate above control values. This was associated with a 2.5-fold increase in insulin-mediated cAMP generation (52 ± 3 pmol ⋅ mg protein−1 ⋅ 5 min−1). Genistein, a tyrosine kinase inhibitor, diminished insulin-stimulated Mg2+ uptake (169 ± 11 nM/s), but did not change insulin-mediated cAMP formation (47 ± 5 pmol ⋅ mg protein−1 ⋅ 5 min−1). PTH stimulates Mg2+ entry, in part, through increases in cAMP formation. Insulin and PTH increase Mg2+ uptake in an additive fashion. In conclusion, insulin mediates Mg2+ entry, in part, by a genistein-sensitive mechanism and by modifying hormone-responsive transport. These studies demonstrate that insulin stimulates Mg2+ uptake in MDCT cells and suggest that insulin acts in concert with other peptide and steroid hormones to control magnesium conservation in the distal convoluted tubule.

scholarly journals Kinetic and physicochemical characteristics of an endogenous inhibitor to progesterone–receptor binding in rat placental cytosol

1981 ◽  
Vol 199 (2) ◽  
pp. 371-381 ◽  
Author(s):  
T F Ogle
Keyword(s):  
Progesterone Receptor ◽  
Receptor Binding ◽  
Binding Sites ◽  
Fold Increase ◽  
Dissociation Rate ◽  
Energy Of Activation ◽  
Gel Chromatography ◽  
Dependent Manner ◽  
Endogenous Inhibitor ◽  
Concentration Dependent Manner

This study describes the kinetic behaviour and physicochemical aspects of an endogenous inhibitor of progesterone--receptor binding in trophoblast cytosol from day-12 embryos. The progesterone cytosol receptor was partially purified and isolated from the inhibitor as the 0--50%-satd. (NH4)2SO4 fraction. The inhibitory substance was shown to reside in the 50--70%-satd. (NH4)2SO4 fraction. Equilibration of the inhibitor preparation with the receptor fraction increased the Kapp.D of the ligand--receptor binding reaction in a concentration-dependent manner (26 +/- 3-fold increase in Kapp.D per mg of protein of the (NH4)2SO4 fraction, n = 16). However, the inhibitor did not alter the concentration of binding sites. Studies of other physicochemical aspects of the inhibitor showed it to be non-diffusible, excluded from Sephadex G-25, stable at 35 degrees C for 30 min, but irreversibly denatured at 70 degrees C for 30 min. The Stokes′ radius was estimated by gel chromatography to be 2.8 +/- 0.11 nm (n = 5). Inhibitory activity was destroyed by HgCl2, suggesting that disulphide bridges play an essential role in the biological activity of this molecule. The inhibitor is a macromolecule which does not bind progesterone and differs from albumin. The kinetic mechanism by which the inhibitor enhanced Kapp.D was investigated by measuring association and dissociation rate constants and the energy of activation (Ea) for each reaction. The association rate (k+1) for progesterone and receptor was (1.3 +/- 0.2) x 10(4) M-1 . s-1 but declined to (0.4 +/- 0.1) x 10(4) M-1 . s-1 (n = 5) when exposed to the inhibitor (P less than 0.01). The dissociation rate (k-1) was (3.2 +/- 0.6) x 10(-5) s-1 for progesterone--receptor complex and was unchanged by the inhibitor. The Ea for the association of complex was 33.6 +/- 4.2 kJ/mol and was increased to 63.0 +/- 8.4 kJ/mol by the inhibitor (P less than 0.05). The Ea of dissociation was unaltered. Thus, an inhibitor is present in trophoblast cytosol which specifically enhances Kapp.D without altering availability of binding sites. The mode of action of inhibitor is to increase the energy of activation for association of complex without influencing the dissociation reaction.

A long-lasting, plasmin-activatable thrombin inhibitor aids clot lysis in vitro and does not promote bleeding in vivo

2009 ◽  
Vol 101 (05) ◽  
pp. 867-877 ◽  
Author(s):  
Louise Eltringham-Smith ◽  
Sharon Gataiance ◽  
Varsha Bhakta ◽  
William Sheffield
Keyword(s):  
Chimeric Protein ◽  
Fold Increase ◽  
Thrombin Inhibitor ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Recombinant Hirudin ◽  
Concentration Dependent Manner ◽  
Shed Blood

SummaryThe leech protein hirudin is a potent inhibitor of thrombin, but clinical use of recombinant hirudin is restricted by haemorrhagic risks, and complicated by hirudin’s rapid clearance from the circulation. We previously employed albumin fusion to slow hirudin variant 3 (HV3) clearance. In this study, we hypothesized that reconfiguration of the chimera, appending human serum albumin (HSA) to the N-terminus of HV3, with an intervening plasmin cleavage site, would create a slowly cleared, plasmin-activatable HV3. Potential plasmin cleavage sites were screened by expression in Escherichia coli, interposed between glutathione sulfotransferase and HV3 domains. The most reactive sequence (GSGIYR-ITY) was recreated in C-terminally His-tagged albumin fusion protein HSACHV3, expressed in Pichia pastoris yeast and purified by nickel-chelate affinity chromatography. HSACHV3 showed no thrombin inhibitory activity in the absence of plasmin, but liberated active HV3 in a time- and concentration-dependent manner in its presence. In a discontinuous clot assay involving clot-bound thrombin, HSACHV3 assisted clot lysis by limiting clot extension in a tPA- and concentration-dependent manner. Similar results were obtained in plasma at higher concentrations of HSACHV3. The chimeric protein exhibited much slower clearance in mice than unfused HV3, and indistinguishable pharmacokinetics from unfused recombinant HSA. In a mouse tail transection bleeding model, doses of HSACHV3 identical to those of HV3 that elicited a four-fold increase in the volume of shed blood were without effect. Our results suggest that HSACHV3 is a fully latent, plasmin activatable, long-lasting hirudin, of potential benefit in thrombotic disorders resistant to natural or pharmacological clot lysis.

scholarly journals Plasmatic and cell-based enhancement of in vitro induced coagulopathy by microparticles originated from platelets and endothelial cells

2020 ◽  
Author(s):  
Julia Boehm ◽  
Nadine Schäfer ◽  
Marc Maegele ◽  
Birgit Stümpges ◽  
Ursula Bauerfeind ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Platelet Activation ◽  
Fibrin Clot ◽  
Dependent Manner ◽  
Clotting Factors ◽  
Concentration Dependent Manner ◽  
Coagulation Process ◽  
Lethal Triad ◽  
Plasmatic Coagulation

Abstract Background: Aggressive trauma management and other external factors lead to hypothermia, acidosis and hemodilution (defined as Lethal Triad, LT) contributing to coagulopathy after trauma (Trauma-induced coagulopathy, TIC) that worsens patients’ outcomes. Procoagulative microparticles (MP) are crucial players at the interface of cellular and plasmatic coagulation. However, their functions remain largely unexplored. This study aimed to characterize effects of MP subtypes and concentrations on functional coagulation under in vitro simulated conditions. Methods: Blood from eleven volunteers were collected to simulate in vitro conditions of haemodilution (HD) and LT, respectively. HD was induced by replacing a blood volume of 33% by crystalloids and for LT, samples were further processed by reducing the temperature to 32 °C and lowering the pH to 6.8. MP were obtained either from platelet concentrates (platelet-derived MP, PDMP) or from cell culture (ECV304 cells for endothelial-derived MP, EDMP) by targeted stimulation. After introducing MP to in vitro conditions, their concentration-dependent effects (1.000, 10.000 and 15.000 MP/µl blood) on coagulation compared to whole blood (WB) were characterized by flow cytometric platelet activation and by quantification of fibrin clot propagation and spontaneous clotting using Thrombodynamics® technology.Results: MP originated from platelets and endothelial cells affected blood coagulation in a concentration-dependent manner. Particularly, high PDMP quantities significantly induced platelet activation and fibrin clot growth and size in HD conditions. In LT conditions, the highest PDMP concentration enhanced platelet activation, clot growth and size. In contrast, EDMP supplementation did not affect platelet activation, but resulted in enhanced formation of spontaneous clots, irrespective of simulated condition. With increasing EDMP concentration, the time until the onset of spontaneous clotting decreased in both HD and LT conditions.Discussion: The study demonstrates an essential role of MP within the coagulation process under simulated coagulopathic conditions. While PDMP affected platelets promoting clot formation likely by providing a surface enlargement, EDMP presumably affected clotting factors of the plasmatic coagulation resulting in an increased formation of spontaneous fibrin clots.Conclusion: The diverse effects of in vitro generated MP from different cellular origin indicate a divergent mechanism of action exhibiting distinct functions within the coagulation process.

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