scholarly journals Anticoagulant Properties of a Green Algal Rhamnan-type Sulfated Polysaccharide and Its Low-molecular-weight Fragments Prepared by Mild Acid Degradation

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 445 ◽  
Author(s):  
Xue Liu ◽  
Peng Du ◽  
Xiao Liu ◽  
Sujian Cao ◽  
Ling Qin ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Anticoagulant Activity ◽  
Sulfated Polysaccharide ◽  
Low Molecular Weight ◽  
Thrombin Time ◽  
Acid Degradation ◽  
Molecular Weights ◽  
Green Algal

The active sulfated polysaccharide from seaweed possesses important pharmaceutical and biomedical potential. In the study, Monostroma sulfated polysaccharide (MSP) was obtained from Monostroma angicava, and the low-molecular-weight fragments of MSP (MSP-Fs: MSP-F1–MSP-F6) were prepared by controlled acid degradation. The molecular weights of MSP and MSP-F1–MSP-F6 were 335 kDa, 240 kDa, 90 kDa, 40 kDa, 24 kDa, 12 kDa, and 6.8 kDa, respectively. The polysaccharides were sulfated rhamnans that consisted of →3)-α-l-Rhap-(1→ and →2)-α-l-Rhap-(1→ units with partial sulfation at C-2 of →3)-α-l-Rhap-(1→ and C-3 of →2)-α-l-Rhap-(1→. Anticoagulant properties in vitro of MSP and MSP-F1–MSP-F6 were evaluated by studying the activated partial thromboplastin time, thrombin time, and prothrombin time. Anticoagulant activities in vivo of MSP and MSP-F4 were further evaluated; their fibrin(ogen)olytic activities in vivo and thrombolytic properties in vitro were also assessed by D-dimer, fibrin degradation products, plasminogen activator inhibitior-1, and clot lytic rate assays. The results showed that MSP and MSP-F1–MSP-F4 with molecular weights of 24–240 kDa had strong anticoagulant activities. A decrease in the molecular weight of MSP-Fs was accompanied by a decrease in the anticoagulant activity, and higher anticoagulant activity requires a molecular weight of over 12 kDa. MSP and MSP-F4 possessed strong anticoagulant activities in vivo, as well as high fibrin(ogen)olytic and thrombolytic activities. MSP and MSP-F4 have potential as drug or helpful food supplements for human health.

Toxicity of Heparinoids, with Special Reference to the Precipitation of Fibrinogen

1964 ◽  
Vol 12 (01) ◽  
pp. 232-261 ◽  
Author(s):  
S Sasaki ◽  
T Takemoto ◽  
S Oka
Keyword(s):  
Molecular Weight ◽  
Dextran Sulfate ◽  
Anticoagulant Activity ◽  
Molecular Structures ◽  
Severe Reaction ◽  
Clinical Use ◽  
Molecular Weights ◽  
Close Relationship

SummaryTo demonstrate whether the intravascular precipitation of fibrinogen is responsible for the toxicity of heparinoid, the relation between the toxicity of heparinoid in vivo and the precipitation of fibrinogen in vitro was investigated, using dextran sulfate of various molecular weights and various heparinoids.1. There are close relationships between the molecular weight of dextran sulfate, its toxicity, and the quantity of fibrinogen precipitated.2. The close relationship between the toxicity and the precipitation of fibrinogen found for dextran sulfate holds good for other heparinoids regardless of their molecular structures.3. Histological findings suggest strongly that the pathological changes produced with dextran sulfate are caused primarily by the intravascular precipitates with occlusion of the capillaries.From these facts, it is concluded that the precipitates of fibrinogen with heparinoid may be the cause or at least the major cause of the toxicity of heparinoid.4. The most suitable molecular weight of dextran sulfate for clinical use was found to be 5,300 ~ 6,700, from the maximum value of the product (LD50 · Anticoagulant activity). This product (LD50 · Anticoagulant activity) can be employed generally to assess the comparative merits of various heparinoids.5. Clinical use of the dextran sulfate prepared on this basis gave satisfactory results. No severe reaction was observed. However, two delayed reactions, alopecia and thrombocytopenia, were observed. These two reactions seem to come from the cause other than intravascular precipitation.

INFLUENCE OF THE SULFATION PATTERN ON CERTAIN BIOLOGICAL PROPERTIES OF GALACTOSAMINOGLYCANS

1987 ◽  
Author(s):  
B Casu ◽  
L Marchese ◽  
A Naggi ◽  
G Torri ◽  
J Fareed ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Dermatan Sulfate ◽  
Anticoagulant Activity ◽  
Chlorosulfonic Acid ◽  
Biological Properties ◽  
Sulfated Polysaccharides ◽  
Low Molecular Weight ◽  
Antithrombotic Activity

In order to investigate the influence of charge distribution and chain length on the biological properties of sulfated polysaccharides, additional sulfate groups were introduced into the galactosaminoglycans, chondriotin sulfate and dermatan sulfate. Using a flexible method (with sulfuric acid and chlorosulfonic acid) for concurrent sulfation and controlled depolymerization, numerous products were obtained and characterized by chemical, enzymatic and nuclear magnetic resonance spectroscopic methods. The biologic actions of these products were profiled in both in vitro and in vivo assays for antithrombotic activity. Despite a weaker in vitro anticoagulant activity, low molecular weight over sulfated galactosaminoglycans produced significant dose-dependent antithrombotic actions in animal models which were similar to the actions observed with oversulfated low molecular weight heparins. These results suggest that a significant antithrombotic activity can be elicited through non-specific interactions of polysulfates with cellular and plasma components, and that clusters of sulfate groups such as the 4-6 disulfate group on D-galactosaminoglycan residues may be important for these interactions. Furthermore, these results, also suggest that supersulfation of glycosaminogly-cans results in products with biologic activity distinct from the native material.

Effect of 1,6-Anhydro Bicyclic Ring Structure on the Pharmacokinetic and Pharmacodynamic Behavior of Low Molecular Weight Heparin.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1868-1868 ◽  
Author(s):  
Walter P. Jeske ◽  
Brian Neville ◽  
Qing Ma ◽  
Debra A. Hoppensteadt ◽  
Jawed Fareed
Keyword(s):  
Molecular Weight ◽  
Half Life ◽  
Low Molecular Weight Heparin ◽  
Anticoagulant Activity ◽  
Plasma Concentrations ◽  
Significant Proportion ◽  
Low Molecular Weight ◽  
Antithrombin Activity

Abstract Introduction: Heparin cleavage under alkaline conditions results in low molecular weight heparin (LMWH) chains, a significant proportion of which contain 1,6-anhydromannosamine and/or 1,6-anhydroglucosamine at the reducing end. Despite the widespread use of the LMWHs for the prophylaxis and treatment of thrombosis, it remains unclear whether such structural modifications impact the pharmacologic activity of the drug. This study examined the in vitro anticoagulant and in vivo pharmacokinetic/pharmacodynamic (PK/PD) behavior of LMWHs containing varying levels of 1,6-anhydrosugar content. Materials and Methods: By altering the temperature and pH of the depolymerization reaction, LMWHs containing 0, 5, 10, 20 and 40% 1,6-anhydrosugar were produced. These compounds were supplemented to normal human plasma and normal primate plasma and assayed for anticoagulant (APTT and Heptest) and antiprotease (anti-IIa and anti-Xa) activity. The effect of 1,6-anhydrosugar on the PK/PD profile of LMWHs was assessed by administering the 40% 1,6-anhydro LMWH or enoxaparin (~20% 1,6-anhydrosugar) intravenously to groups of non-human primates (n=4–6) at a dose of 1 mg/kg. Blood samples were collected at baseline and at various time points up to 24 hours post-administration for determination of Heptest clotting times, anti-IIa and anti-Xa activity. The biologic activities were converted to equivalent LMWH concentrations using calibration curves prepared in normal primate plasma. Results: The molecular weight profiles of these LMWHs were comparable. No effect on anticoagulant or antiprotease activity was observed when the 1,6-anhydro content varied between 0 and 10%. When the 1,6-anhydro content was increased to 20 and 40%, a content-dependent reduction in anticoagulant activity was observed such that the prolongation of the APTT and Heptest by the 40% 1,6-anhydro LMWH was 58 and 23% less, respectively, than that produced by the LMWH lacking the 1,6-anhydro group when tested in the linear range of the concentration-response curve. This effect appears to be related primarily to an interference with antithrombin activity. Inhibition of thrombin activity in an amidolytic assay was 35% lower with the 40%-anhydro LMWH compared to the 0% anhydro compound (10 mg/ml), whereas anti-Xa activity was only 7% lower. Assay dependent variations were observed in the PK/PD profiles of the 40% anhydro LMWH and enoxaparin. As expected, the half-life of antithrombin activity was considerably shorter than that of the anti-Xa activity. The pharmacokinetic behavior of the 40% 1,6-anhydro LMWH and enoxaparin in terms of half-life, area under the curve, systemic clearance and volume of distribution was not significantly different when calculated using plasma concentrations determined by anti-IIa or anti-Xa assay. When concentrations determined by Heptest were used, the AUC determined for enoxaparin was approximately 2-fold higher than that determined with the 40% anhydro LMWH. Conclusions: Microchemical changes in the structure of low molecular weight heparin oligosaccharides can induce measurable changes in the biologic activity of LMWHs. While the pharmacokinetic profile does not appear to be altered by an enhanced 1,6-anhydro content, the effect of 1,6-anhydro content on the clinical efficacy and safety of LMWHs is unknown. Such findings may have particular impact on the development of generic LMWHs.

In Vitro Characterization of the Neutralization of Unfractionated Heparin and Low Molecular Weight Heparin by Novel Salicylamide Derivatives.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1869-1869
Author(s):  
Walter Jeske ◽  
Aleah Brubaker ◽  
Dahui Liu ◽  
Trevor Young ◽  
Debra Hoppensteadt ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Anticoagulant Activity ◽  
Protamine Sulfate ◽  
In Vitro Assays ◽  
Low Molecular Weight ◽  
Dependent Manner ◽  
Thrombin Time ◽  
Salicylamide Derivatives

Abstract Introduction: Unfractionated heparin and the low molecular weight heparins (LMWHs) are commonly used in the treatment of acute coronary syndromes, as prophylaxis against deep vein thrombosis and pulmonary embolism and to prevent clotting during interventional and surgical procedures. The neutralization of unfractionated heparin is critical following the completion of coronary bypass surgery to avoid excessive blood loss. Unfractionated heparin can be neutralized by protamine sulfate, a highly cationic peptide that binds to heparin in a charge-dependent manner. However, the use of protamine can be associated with serious side-effects such as hypotension, bronchoconstriction, or pulmonary hypertension, possibly due to the release of histamine. Additionally, large doses of protamine can produce an anticoagulant effect. This study characterizes the ability of a series of low molecular weight, homogeneous, synthetic, polycationic salicylamide derivatives (PolyMedix, Radnor, PA) to neutralize the anticoagulant actions of unfractionated heparin and enoxaparin. Methods: Human plasma was supplemented with unfractionated heparin or enoxaparin (Sanofi-Aventis, Paris, France) at a concentration of 10 μg/ml. Protamine sulfate or one of six of the structurally distinct salicylamide derivatives was added to aliquots of heparinized plasma to achieve final concentrations of 50, 25 and 12.5 μg/ml. The supplemented plasmas were immediately analyzed using clotting (aPTT, Heptest, thrombin time) and amidolytic (anti-Xa, anti-IIa) assays. Results: Using the in vitro assays, protamine sulfate was shown to concentration-dependently neutralize the actions of unfractionated heparin in all of the assays. Two of the salicylamide derivatives tested produced an effect comparable to protamine, while three derivatives exhibited a relatively stronger neutralization of unfractionated heparin. The extent of neutralization measured by anti-Xa and anti-IIa assays was also greater with the derivatives. While residual anti-Xa and anti-IIa activities (20% and 10%, respectively) were observed even with a 5-fold gravimetric excess of protamine, complete neutralization was observed with the salicylamide derivatives. Protamine is known to be less effective at neutralizing LMWHs. In this study, the anticoagulant activity of enoxaparin as measured by aPTT and Heptest was neutralized approximately 50% by protamine even at a 5:1 protamine to enoxaparin ratio. The derivatives were able to completely neutralize the anticoagulant effects of enoxaparin. A similar pattern was observed with the amidolytic assays. While protamine was unable to neutralize the anti-Xa activity of enoxaparin, 5 of the 6 salicylamide derivatives concentration-dependently inhibited the anti-Xa activity. Discussion: These studies demonstrate that the PolyMedix series of salicylamide derivatives can effectively neutralize the anticoagulant and anti-protease actions of unfractionated heparin and LMWHs such as enoxaparin. Initial results suggest that such agents are more effective than protamine at neutralizing other LMWHs. Future studies are designed to characterize the compounds’ PK/PD profiles. These results warrant further studies on the neutralization profile of PolyMedix series of salicylamide derivatives in animal models of bleeding and thrombosis.

In Vivo Evaluation Of The Antithrombotic Effects Of Some Polysaccharides Of Ultra Low Molecular Weight

1981 ◽  
Author(s):  
J Fareed ◽  
H L Messmore ◽  
J Choay ◽  
C Lormeau ◽  
M Petitou ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Serine Proteases ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Thrombin Time ◽  
Prothrombin Complex Concentrates ◽  
In Vivo Evaluation ◽  
Activated Prothrombin Complex Concentrates

Ultra low molecular weight saccharide fragments (ULMFs) have been obtained from porcine mucosal heparin (PMH) by extraction (e-ULMF) and by bacterial heparinase depolymerization (h-ULMF-8) processes. Both fragments showed a strong anti Xa activity (>2000 u/mg units, Yin and Wessler, J. Lab. Clin. Med. 81, 298, 1973) and possess relatively weak potencies in the US Pharmacoepial (<40 USP u/mg) and other conventional coagulant assays (activated and non activated partial thromboplastin time, thrombin time and whole blood activated recalcification times). Since ULMFs showed a strong anti Xa activity, we evaluated their antithrombotic actions in a modified stasis-thrombosis model (Wessler et. al. J. App. Phys. 14, 943, 1959) challenging the animals with various thrombogenic stimuli; activated and non activated prothrombin complex concentrates, factor Xa concentrates and human serum. h-ULMF-8 at dosage <0.125 mg/kg (<250 Anti Xa u/kg) IV and <1.0 mg/kg (>2000 anti Xa u/kg) SC completely protected the thrombogenic effects of various thrombogenic agents, whereas PMH at these dosages failed to produce any protection in pre and post treatment regiments. Similar studies with e-ULMF showed protection, however, the antithrombotic responses varied among animals. In vitro supplementation of heparin fragments at 5 times the concentration which protected animals against the thrombogenic effects of activated prothrombin complex concentrates failed to produce any elevation of prothrombin time, partial thromboplastin times, thrombin time and other coagulant assays. Our studies suggest that ULMFs are potent antithrombotic agents and may exert their effects involving multiple sites and primarily inhibiting the Xa and the non-thrombin serine proteases formed during activated states.

Dose Response Relationships of Anticoagulant Activities After Subcutaneous Administration of Two Low Molecular Weight Heparins in Healthy Individuals

1986 ◽  
Vol 56 (02) ◽  
pp. 225-228 ◽  
Author(s):  
P Hellstern ◽  
R Kiehl ◽  
G von Blohn ◽  
M Köhler ◽  
U Meierhenrich ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Platelet Function ◽  
Subcutaneous Administration ◽  
Thrombosis Prophylaxis ◽  
Low Molecular Weight ◽  
Thrombin Time ◽  
Healthy Individuals ◽  
Low Molecular Weight Heparins

SummaryThis study was performed to estimate appropriate dosages of two low molecular weight heparins (LMWH) for clinical trials on subcutaneous perioperative thrombosis prophylaxis. Anticoagulatory activities and platelet function were investigated after single doses of two LMWH and of unfractionated sodium heparin (UFH) in 24 healthy individuals. Twelve subjects received subcutaneous injections of 1000, 1500, and 2500 i.u. (aPTT) of LMHW 1, and the other 12 received LMWH 2 at same dosages. The following parameters were determined before 30 min, 1 h, 90 min, 2 h, 3 h, 4 h, 6 h, 8 h, and 10 h after either LMWH or 5000 i.u. (aPTT) UFH: aPTT, thrombin time, anti-Xa activity (S 2222, Coatest heparin), and anti-IIa activity (Chromozym TH). Bleeding time, platelet count, and adrenalin-, collagen-, and ADP-induced platelet aggregation were assessed before and 3 h after administration.After application of 1500 i.u. LMWH 1 and LMWH 2, the anti-Xa and anti-IIa levels were already significantly higher than after 5000 i.u. UFH. 2500 i.u. LMWH 1 and LMWH 2 evoked significantly greater prolongations of aPTT and thrombin time values than did 5000 i.u. UFH. This was not the case after 1000 and 1500 i.u. LMWH. The half-lives of anticoagulatory effects after LMWH were markedly longer than after UFH. Platelet function was not altered by any of the heparins tested. Our results indicate that LMWH cause anticoagulatory effects in vivo that cannot be predicted by in vitro studies and that the appropriate single dosages of LMWH in subcutaneous perioperative thrombosis prophylaxis have to be estimated by dosage determinations in healthy subjects.

scholarly journals Studies with High and Low Molecular Weight Tritium-Labelled Heparin in Vivo and in Vitro

1977 ◽  
Author(s):  
J. N. Shanberge ◽  
S. Ambegaonkar ◽  
T. Kitani ◽  
M. Gruhl ◽  
J. Kambayashi ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Anticoagulant Activity ◽  
Lower Molecular Weight ◽  
Low Molecular Weight ◽  
Clotting Time ◽  
Platelet Poor Plasma ◽  
Antithrombin Activity ◽  
Molecular Weight Fractions

When defibrinated platelet-poor plasma 1s chromatographed on Sephadex G-200, fractions with antithrombin-heparin cofactor activity are found 1n only one area. When platelet-poor plasma treated with a tritium-labelled heparin is chromatographed on Sephadex G-200, radioactivity, signifying the presence of heparin, is spread across all of the protein fractions, whereas immediate antithrombin activity is located in two. main areas. Tritiated heparin produced from porcine intestinal mucosa was fractionated on a Sephadex G-200 column with separation of the higher and lower molecular weight fractions. These fractions were added to platelet-poor plasma which was then rechromatographed on Sephadex G-200.With the higher molecular weight, heparin radioactivity appeared in fractions which usually have immediate antithrombin activity, whereas, with the lower molecular weight heparin, it did not. A comparison of the activities of the higher and lower molecular weight material was made after intravenous injection into rats. The higher molecular weight heparin gave higher concentrations of radioactivity in the liver and blood. In addition, the anticoagulant activity as measured by a whole blood recalcification clotting time was maintained for a much longer period. The lower molecular weight heparin was excreted more rapidly in the urine. It is concluded that only the higher molecular weight heparins have anticoagulant activity 1n combining with antithrombin whereas lower molecular weight heparins do not combine with antithrombin but are eliminated in the urine.

scholarly journals Structural Characteristics and Anticoagulant Property In Vitro and In Vivo of a Seaweed Sulfated Rhamnan

Marine Drugs ◽  
2018 ◽  
Vol 16 (7) ◽  
pp. 243 ◽  
Author(s):  
Xue Liu ◽  
Shuyao Wang ◽  
Sujian Cao ◽  
Xiaoxi He ◽  
Ling Qin ◽  
...  
Keyword(s):  
Degradation Products ◽  
Structural Characteristics ◽  
Anticoagulant Activity ◽  
Sulfated Polysaccharide ◽  
Thrombin Time ◽  
Drug Molecules ◽  
Monostroma Angicava ◽  
Anticoagulant Property

Great diversity and metabolite complexity of seaweeds offer a unique and exclusive source of renewable drug molecules. Polysaccharide from seaweed has potential as a promising candidate for marine drug development. In the present study, seaweed polysaccharide (SPm) was isolated from Monostroma angicava, the polymeric repeat units and anticoagulant property in vitro and in vivo of SPm were investigated. SPm was a sulfated polysaccharide which was mainly constituted by 3-linked, 2-linked-α-l-rhamnose residues with partially sulfate groups at C-2 of 3-linked α-l-rhamnose residues and C-3 of 2-linked α-l-rhamnose residues. Small amounts of xylose and glucuronic acid exist in the forms of β-d-Xylp(4SO4)-(1→ and β-d-GlcA-(1→. SPm effectively prolonged clotting time as evaluated by the activated partial thromboplastin time and thrombin time assays, and exhibited strong anticoagulant activity in vitro and in vivo. The fibrin(ogen)olytic and thrombolytic properties of SPm were evaluated by plasminogen activator inhibitior-1, fibrin degradation products, D-dimer and clot lytic rate assays using rats plasma, and the results showed that SPm possessed high fibrin(ogen)olytic and thrombolytic properties. These results suggested that SPm has potential as a novel anticoagulant agent.

Effects of Unfractionated and Low Molecular Weight Heparins on Platelet Thromboxane Biosynthesis “In Vivo”

1994 ◽  
Vol 72 (06) ◽  
pp. 942-946 ◽  
Author(s):  
Raffaele Landolfi ◽  
Erica De Candia ◽  
Bianca Rocca ◽  
Giovanni Ciabattoni ◽  
Armando Antinori ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Primary Source ◽  
In Vivo Studies ◽  
Low Molecular Weight ◽  
Heparin Administration ◽  
To Receive

SummarySeveral “in vitro” and “in vivo” studies indicate that heparin administration may affect platelet function. In this study we investigated the effects of prophylactic heparin on thromboxane (Tx)A2 biosynthesis “in vivo”, as assessed by the urinary excretion of major enzymatic metabolites 11-dehydro-TxB2 and 2,3-dinor-TxB2. Twenty-four patients who were candidates for cholecystectomy because of uncomplicated lithiasis were randomly assigned to receive placebo, unfractionated heparin, low molecular weight heparin or unfractionaed heparin plus 100 mg aspirin. Measurements of daily excretion of Tx metabolites were performed before and during the treatment. In the groups assigned to placebo and to low molecular weight heparin there was no statistically significant modification of Tx metabolite excretion while patients receiving unfractionated heparin had a significant increase of both metabolites (11-dehydro-TxB2: 3844 ± 1388 vs 2092 ±777, p <0.05; 2,3-dinor-TxB2: 2737 ± 808 vs 1535 ± 771 pg/mg creatinine, p <0.05). In patients randomized to receive low-dose aspirin plus unfractionated heparin the excretion of the two metabolites was largely suppressed thus suggesting that platelets are the primary source of enhanced thromboxane biosynthesis associated with heparin administration. These data indicate that unfractionated heparin causes platelet activation “in vivo” and suggest that the use of low molecular weight heparin may avoid this complication.

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

1995 ◽  
Vol 73 (05) ◽  
pp. 805-811 ◽  
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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