JP2002060345A - Prophylactic and therapeutic agent for disease associated with abnormality in blood coagulation ability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a prophylactic and therapeutic agent for diseases associated with an abnormality in blood coagulation ability by using at least a thrombomodulin (TM)-like protein and a heparin in combination as active ingredients. SOLUTION: This prophylactic and therapeutic agent for the diseases associated with the abnormality in blood coagulation ability is characterized as using the TM-like protein and the heparin in combination as the active ingredients.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a blood coagulation disorder comprising a combination of a thrombomodulin (hereinafter abbreviated as TM) -like protein and heparin or, further, antithrombin III (hereinafter abbreviated as ATIII) as active ingredients. The present invention relates to a prophylactic / therapeutic agent for diseases related to

[0002]

2. Description of the Related Art TM is a glycoprotein that was discovered by Esmon et al. In 1981 as an anticoagulant substance present on the surface of vascular endothelial cells, and subsequently its entire amino acid sequence was revealed in 1987 by Suzuki et al. It is a substance that binds to thrombin and suppresses the procoagulant action of thrombin and remarkably promotes the activation of protein C by thrombin. Since TM-like proteins efficiently suppress the coagulation system and reduce the risk of bleeding, they may be useful for the prevention and treatment of disseminated intravascular coagulation syndrome (hereinafter abbreviated as DIC) and various thrombosis. Is suggested. On the other hand, heparin is a strong organic acid mucopolysaccharide with many sulfate groups,
It is a powerful anticoagulant. The anticoagulant effect of heparin is based on the fact that heparin enhances the inhibitory effect of ATIII in blood on thrombin or activated blood coagulation factor X. For this reason, it is said that when the ATIII activity is reduced to 70% or less, the effect is reduced. As for heparin, heparin calcium and heparin sodium are DI
C is commercially available for indications such as therapeutic agents, but it includes bleeding, shock, heparin-induced thrombocytopenia (hereinafter abbreviated as HIT), and heparin-induced thrombocytopenia (hereinafter, HITT).
S, which is abbreviated as S), and the interaction with other anticoagulants, thrombolytic agents, or antiplatelet agents increases the bleeding tendency, which is a problem. Therefore, monitoring of coagulation time is essential to avoid serious side effects such as bleeding.

[0003] Dalteparin sodium (low molecular weight heparin) is commercially available for use as a therapeutic agent for DIC. This is a collection of low molecular weight fractions of heparin, which has almost the same anti-activated blood coagulation factor X activity as that of conventional heparin, but has a large deviation from the anti-thrombin action and has a large activation partial thromboplastin. Time (hereinafter, AP
It is said that the prolonged activity is low and the risk of bleeding is low, but it is not always clinically sufficient. In addition, since the half-life is short, in DIC treatment, administration by continuous intravenous infusion is basically the same as conventional heparin. Heparin and low-molecular-weight heparin are cautioned to be used in combination with other anticoagulants.

[0004] A TM-like protein is a substance that binds to thrombin and suppresses the procoagulant action of thrombin and remarkably promotes the activation of protein C by thrombin. Since the TM-like protein efficiently suppresses the coagulation system, it has been suggested that the TM-like protein is useful for prevention and treatment of DIC and various thrombosis. The combined effect of TM-like protein and heparin on the anticoagulant effect is not known. However, since heparin promotes the binding of ATIII to thrombin, it was expected that the anticoagulant effect due to the binding of the TM-like protein to thrombin would be reduced. In addition, it has been reported that heparin promotes the inhibitory activity of activated protein C activity by a protein C inhibitor by 20 times or more (Journal of Biological Chemistry).
medical Chemistry), 270 volumes, 43
No. 25336-25339 (1995)), which was expected to suppress the anticoagulant action of TM-like protein via activated protein C. Therefore, it has been considered that the combined use of a TM-like protein and heparin may be rather unfavorable as prevention and treatment of diseases related to abnormal blood coagulation ability.

[0005]

As an agent for preventing or treating diseases associated with abnormal blood coagulation, it is more effective than the above-mentioned administration of TM-like protein alone or heparin alone, and has few side effects such as bleeding and safety. Is required. Accordingly, the present invention is a prophylactic / therapeutic agent for a disease associated with abnormal blood coagulation caused by various causes,
It is an object of the present invention to provide a pharmaceutical composition which is more effective than M-like protein alone or heparin alone, is effective for patients with reduced ATIII activity, and has higher safety. In addition, side effects observed when each drug is administered alone, especially bleeding due to heparin, shock, HIT
It is another object of the present invention to provide a pharmaceutical composition for suppressing the occurrence of side effects such as HITTS.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies on a prophylactic / therapeutic agent for a disease associated with abnormal blood coagulation ability. As a result, surprisingly, the present inventors have found that a TM-like protein and heparin alone can be used alone. The present inventors have found that a strong anticoagulant activity, which cannot be obtained by administration, is obtained, and that the tendency of bleeding is not enhanced. Thus, the present invention has been completed.

Hereinafter, the present invention will be described in detail. A first aspect of the present invention is a prophylactic / therapeutic agent for a disease associated with abnormal blood coagulation ability, wherein at least a TM-like protein and heparin are used in combination as active ingredients. As a preventive / therapeutic agent for the disease associated with abnormal blood coagulation ability, an embodiment in which the TM-like protein is a soluble TM-like protein, in particular, an embodiment in which the TM-like protein is a human urine-derived soluble TM-like protein or a recombinant human soluble TM-like protein Is preferred. Further, an embodiment in which heparin is heparin calcium, heparin sodium or dalteparin sodium and enoxaparin (low molecular weight heparin) is preferable. In addition, T which constitutes a prophylactic / therapeutic agent for the disease associated with abnormal blood coagulation ability
It provides both an embodiment in which the M-like protein and heparin are administered simultaneously and an embodiment in which they are administered separately. Examples of diseases associated with abnormal blood coagulation ability include deep vein thrombosis and DIC.

[0008] A second aspect of the present invention is a prophylactic / therapeutic agent for diseases associated with abnormal blood coagulation, characterized by using at least a TM-like protein, heparin and ATIII as active ingredients in combination. Preferred embodiments of the TM-like protein and heparin are the same as described above. The present invention also provides both a mode in which the TM-like protein, heparin, and ATIII constituting the agent for preventing or treating the disease associated with abnormal blood coagulation ability are administered simultaneously, and a mode in which they are separately administered. Diseases associated with abnormal blood coagulation are particularly deep vein thrombosis or D
An IC is exemplified. Further, the present invention provides a method for preventing and treating a disease associated with abnormal blood coagulation ability or a TM-like protein for preventing and treating a disease associated with abnormal blood coagulation ability, comprising a combination of an effective amount of a TM-like protein and heparin. Embodiments in which an effective amount of heparin is used in combination are also included. The effective amount may be within a range in which a preventive / therapeutic effect for a disease relating to abnormal blood coagulation ability can be obtained. The dosage form, administration method, number of administrations per day, degree of symptoms, degree of side effects, APTT value, The dose can be appropriately increased or decreased depending on conditions such as body weight, age, dose ratio of TM-like protein and heparin, simultaneous administration or sequential administration, and the order of administration, but the range of the maximum recommended dose or less is preferable.

[0009] The prophylactic / therapeutic agent of the present invention prevents or prevents diseases associated with abnormal blood coagulation, particularly deep vein thrombosis or DIC, without increasing the bleeding tendency as compared with the administration of TM-like protein or heparin alone. The therapeutic effect can be enhanced. It is also expected to be effective in heparin ineffective cases and patients with reduced ATIII activity. In addition, since the combined use can reduce the dose of each drug, it is expected to suppress the side effects observed when each of the drugs is administered alone. In particular, the combined use of TM-like protein and low-dose heparin is expected. Bleeding from heparin,
Because it is expected to suppress the occurrence of side effects such as shock, HIT and HITTS,
It can be a therapeutic agent.

In the present invention, the term “TM-like protein” is
It refers to TM and peptides having an amino acid sequence of a part necessary for the biological activity of TM or analogs thereof. That is, the TM-like protein used in the present invention includes all proteinaceous substances that bind to thrombin to suppress the procoagulant action of thrombin and remarkably promote protein C activation by thrombin. Therefore, either a natural type or a product produced by genetic engineering may be used, and a modified type or chimeric type obtained by genetic engineering techniques may be used.

In the case of a pharmaceutical, a TM-like protein derived from human (hereinafter abbreviated as human TM-like protein) is preferable.
Further, in the present invention, a highly soluble TM-like protein (hereinafter abbreviated as a soluble TM-like protein), for example, a natural human urine-derived soluble TM-like protein or a human soluble TM-like protein obtained by genetic recombination is further included. preferable. In addition, various TM-like proteins having partial structures of the amino acid sequence of TM, which are produced by using gene recombination technology, also bind to thrombin to suppress the procoagulant action of thrombin and to inhibit protein C activity by thrombin. Those having an effect of remarkably promoting conversion can be used in the present invention.

In the present invention, the term "heparin" refers to D-
N-sulfate, N-acetyl and O-sulfate substituted polysaccharides of glucosamine, D-glucuronic acid and L-iduronic acid, which promote ATIII inhibition of thrombin and blood coagulation factors Xa, VIIa, IXa, etc. All of the mucopolysaccharides having Heparin calcium, heparin sodium and dalteparin sodium and enoxaparin (low molecular weight heparin) which can be administered as pharmaceuticals are exemplified as preferred. These can be purchased as commercial products, or can be purified and obtained by a known method.

In the present invention, the term "ATIII" includes all glycoproteins whose inhibitory activities on thrombin and blood coagulation factor Xa are promoted in the presence of heparin. In the present invention, those that can be administered as a pharmaceutical are preferable,
Dry concentrated human AT available commercially in Japan
III is exemplified. ATIII can be purified and obtained from human plasma or the like by genetic engineering by a known method, and these can also be used.

In the present invention, the term "combination" refers to a TM-like protein, which is an active ingredient of a preventive / therapeutic agent for a disease associated with abnormal blood coagulation ability of the present invention, and heparin, or further ATIII. Simultaneous administration of these multiple agents, or simultaneous administration of the multiple agents, or simultaneous administration of a TM-like protein and heparin or further ATIII in the form of a single agent mixed with ATIII Is included. Here, the plurality of agents may be a two- or three-drug composition in which the TM-like protein and heparin, or furthermore, ATIII are separately contained, and such two or three agents may be combined with the TM-like protein and heparin, Alternatively, three or four or more agents may be used together with other agents comprising various optional components described later without containing ATIII. Furthermore, TM-like protein, heparin or A
The agent containing TIII itself may be a plurality of agents having different optional components contained therein. In addition, as the form of the above-mentioned sequential administration, for example, when the preventive / therapeutic agent for a disease associated with abnormal blood coagulation ability of the present invention is composed of two agents each containing a TM-like protein and heparin separately, Administering one of the two agents containing the TM-like protein first and then administering the other agent containing heparin, or one of the multiple agents containing heparin Is administered first, and then the other containing the TM-like protein is administered. The present invention also includes a single preparation described in the method of use indicating that the TM-like protein and heparin can be used in combination, or described in a package insert, an advertisement for the product, a pamphlet, or the like.

[0015] In the administration form of the present invention, the effect of heparin is not sufficient in the administration example of heparin, the risk of bleeding due to prolongation of APTT more than 2 times, bleeding from nosebleeds or gums, or other In cases where it is not appropriate to continue or increase the dose of heparin due to the risk of side effects, etc., it is possible to obtain a further clinical effect by using a TM-like protein in combination or to reduce the dose of heparin while maintaining the clinical effect. An example of a use mode of suppressing the occurrence of side effects of heparin, that is, a combination therapy of a TM-like protein and low-dose heparin is exemplified. In addition, in the administration example of the TM-like protein, when the effect of the TM-like protein is not sufficient, a use mode in which a further clinical effect is obtained by using heparin in combination is exemplified. Further, when ATIII is used in combination, before the administration of the TM-like protein and heparin,
It can be administered in the middle, later or simultaneously. It is preferred to administer heparin before or concurrently to patients with reduced ATIII activity.

Since the TM-like protein, heparin and ATIII have different pharmacokinetics, it is desirable to administer them in consideration of this. In addition, in blood coagulation disorders, the amount of blood coagulation factors often deviates significantly from normal values, and if these drugs are used near the maximum recommended dose, or if the patient Is more serious, the administration form of the present invention can be used while monitoring blood coagulation ability. In that case, it is preferable to adjust the dose with heparin having a short half-life in vivo. In addition, to monitor the missing blood coagulation factors directly or indirectly, and to compensate for the missing factors by grasping the patient's blood condition,
More appropriate treatment can be performed.

In the present invention, the term "disease related to abnormal blood coagulation ability" means a disease caused by abnormal blood coagulation ability or a disease associated with abnormal blood coagulation ability. For example, DI
C, septic shock, various thrombosis (arterial thrombosis, venous thrombosis, deep vein thrombosis, sporadic intravascular coagulation), iatrogenic thrombotic vascular occlusion, arterial occlusion, aneurysm, PTCA, PTC
Restenosis after R or angioplasty, various vasculitis, Behcet's disease, anti-phospholipid antibody syndrome, collagen disease, systemic erythematosus, peripheral vascular occlusion, myocardial infarction, angina, pulmonary infarction, acute respiratory distress Disease, ARDS, cerebral infarction, transient ischemic attack, cerebral vasospasm, subarachnoid hematoma, stroke, preeclampsia, liver failure, acute hepatitis, chronic hepatitis, fulminant hepatitis, central hepatic vein occlusion, kidney Insufficiency, nephrotic syndrome, various nephritis,
Diseases based on ischemia-reperfusion injury (reperfusion arrhythmia, damage to organs or tissues after surgery or transplantation, necrotizing enteritis, etc.) and the like.

In the present invention, "side effects of heparin"
The term includes all undesirable effects other than the main effects that occur after administration of heparin. Bleeding (gastrointestinal haemorrhage, cerebral haemorrhage, etc.), shock, HIT and HITTS, hypersensitivity (pruritus, hives, chills, fever, rhinitis, bronchial asthma, lacrimation, etc.), alopecia of the skin, vitiligo or hemorrhagic necrosis, etc. GO
T, elevation of GPT, nausea, anorexia, hypolipidemia,
By long-term administration, osteoporosis or hypoaldosteronism is exemplified.

In the method of preparing the agent for preventing or treating a disease associated with abnormal blood coagulation according to the present invention, TM-like protein and heparin, or further ATIII are used as active ingredients separately or in combination. As long as it is possible, various known pharmaceutical manufacturing methods can be used. Therefore, TM-like proteins and heparin, or even AT
III may be formulated separately or in the form of a single agent obtained by mixing them, whether a suitable carrier or medium generally used, for example, sterile water or saline, vegetable oil, mineral oil, Higher alcohols, higher fatty acids, harmless organic solvents, etc., and human serum albumin purified or engineered as required, excipients, coloring agents, emulsifiers, suspending agents, surfactants, solubilizing agents , An anti-adsorption agent, a stabilizing agent, a preservative, a humectant, an antioxidant, a buffering agent, a tonicity agent, an appropriate combination with any components such as a soothing agent,
Pharmaceutical preparations, such as injections, transdermal absorbents, eye drops, nasal absorbents, and oral preparations, and preferably injections, suitable for effective administration to living organisms can be prepared. The formulation of the injection can be provided, for example, as a lyophilized product or a solution for injection, and particularly preferably provided as a lyophilized product.

The method for administering the preventive / therapeutic agent for diseases relating to abnormal blood coagulation ability of the present invention can be intraarterial injection, intravenous injection, subcutaneous injection, intramuscular injection, etc., intravenous injection or intravenous injection. Continuous administration is preferred. Moreover, subcutaneous administration, intraperitoneal administration, intracisternal administration, and oral administration can be performed as necessary. As an intravenous dose, for example, TM
About 0.01-1000 μg / day
/ Kg, preferably about 0.1 to 500 µg / kg, more preferably 1 to 200 µg / kg, and still more preferably 5 to 100 µg / kg. The TM-like protein is desirably administered at a single intravenous injection or intravenously within several hours. Alternatively, it may be continuously administered intravenously over 24 hours together with heparin. The dosage of heparin calcium or sodium heparin can be administered according to the usage of commercially available heparin calcium or sodium heparin, but is preferably in the range of the maximum recommended dose or less, and about 500 to 30,
000 units, preferably 1,000 to 15,000 units. The dose of dalteparin sodium can be administered according to the usage of commercially available dalteparin sodium, but is preferably in the range of the maximum recommended dose or less, and 10 to 200 international units / kg, preferably 2
0-100 international units / kg are exemplified. Heparin is
It is desirable to continuously administer the above dose intravenously over 24 hours. The prophylactic / therapeutic agent of the present invention is expected to reduce the dose by one-half to one-half as compared with the case of single administration of each drug. In addition, while monitoring the blood coagulation ability of the patient, the dose of each drug can be appropriately increased or decreased.

The dose of ATIII can be administered according to the usage of commercially available dry concentrated human ATIII, but can be appropriately increased or decreased according to the ATIII activity in the blood of the patient, and can be 1,000 to 3,000 daily. The unit is exemplified. In addition, the above-mentioned dosage is determined based on the dosage form, administration method, number of administrations per day, degree of symptoms, degree of side effects, APTT value, body weight, age, the ratio of the dosage of TM-like protein and heparin, and It can be increased or decreased as appropriate according to conditions such as sequential administration or administration order.

[0022]

EXAMPLES The present invention will be described below with reference to experimental examples and examples, but the present invention is not limited to these examples.

Acquisition Example 1 (Acquisition of a soluble TM-like protein derived from human urine) A protein was prepared according to the method described in JP-A-3-218399. That is, 100 L of raw urine was filtered through an acrylic fiber to adsorb and remove urokinase in urine, and the passing urine was desalted and concentrated using an ultrafiltration membrane. Next, purification was performed sequentially using a DEAE cellulose (manufactured by Whatman) column, DIP-thrombin-agarose chromatography, and Sephacryl S-300 (manufactured by Pharmacia Fine Chemical Company) to collect an active fraction (hereinafter, U
Abbreviated as TM). This fraction was dialyzed against distilled water overnight and freeze-dried.

Experimental Example Experimental Example 1 (human normal plasma AP of TM-like protein and heparin)
Influence on TT in vitro) 5 μL of UTM solution (0-1,000 TMU / mL)
For measurement of coagulation time in which 5 μL of a solution of heparin (0 to 2.5 U / mL), low molecular weight heparin (0 to 8 U / mL) or argatroban (0 to 5 μg / mL), which is a synthetic thrombin inhibitor, is previously placed. 50 μl of human normal plasma was added to the cuvette, 50 μl of an APTT measurement reagent (Actin, manufactured by Dade) was added, and the mixture was incubated at 37 ° C. for 2 minutes.
An aCl ₂ solution (50 μl) was added, and the coagulation time was measured using a fully automatic blood coagulation analyzer (KC-40, Amelung).
g) (manufactured by the company). The measurement results are shown in FIGS. If the solidification did not occur within 300 seconds, it was indicated as 300 seconds. When UTM was used in combination with heparin or low-molecular-weight heparin, the anticoagulant action was synergistically enhanced as compared with each of UTM, heparin or low-molecular-weight heparin alone. On the other hand, when UTM and argatroban are used together,
No remarkable potentiating effect was observed in comparison with M or argatroban alone.

Experimental Example 2 (Effect of TM-like Protein and Heparin on DIC Model Rat Induced by Thromboplastin) Male rats (Wistar strain, 7 to 8 weeks old) were used in groups of 5 rats. Anesthetized by intraperitoneal administration of urethane, and 5 mg from the right femoral vein at the time of drug alone administration using a terfusion syringe pump (STC-531, manufactured by Terumo Corporation).
The drug was continuously administered at a volume of ml / kg / hour for 90 minutes at a volume of 2.5 ml / kg / hour for one drug from both femoral veins at the time of drug combination. Thirty minutes after administration of the drug, 1
5 mg / ml thromboplastin (lioplastin,
Mochida Pharmaceutical Co., Ltd.) solution at a volume of 10 ml / kg / hour
It was administered continuously for 0 minutes (total dose 50 mg / kg). The normal control group received each solvent instead of thromboplastin and drug, and the control group received solvent instead of drug. At the end of drug administration, blood was collected from the jugular vein, serum was separated, and fibrin degradation products (hereinafter abbreviated as FDP) were measured using an FDP measurement kit (FDPL test, manufactured by Teikoku Organs Co., Ltd.). In addition, the plasma was separated and APTT was measured in the same manner as in Experimental Example 1. Five minutes after the end of the drug administration, a thin plate IIR (manufactured by Organon Technica) was pressed at a position 4 to 6 cm from the tip of the tail to make an incision. A filter paper was lightly applied to the cut wound every 30 seconds, and the point at which blood adhesion was no longer observed was defined as the hemostatic time. The time from incision preparation to hemostasis time was defined as the bleeding time. Each measurement result was shown in FIGS.

In the control group, administration of thromboplastin was found to increase serum FDP, prolong APTT and prolong bleeding time. Serum F was increased by single administration of UTM or 25 and 50 U / kg of heparin alone.
An increase in the amount of DP and prolongation of the bleeding time were suppressed.
It had no effect on PTT prolongation. The single administration of heparin at 100 U / kg attenuated the increase in serum FDP amount and the effect of suppressing the prolongation of bleeding time, and prolonged APTT. UTM and heparin 25 or 50 U / kg
When combined administration of (1) and (2), compared with the case where the same amount of UTM or heparin was administered alone, the effect of suppressing the increase in the amount of serum FDP was enhanced, but did not affect the effect on bleeding time and APTT prolongation. From the above results, UT
It was shown that the combined use of M and heparin enhances the anti-DIC effect in a range where APTT prolongation is not observed, that is, enhances the anti-DIC effect without enhancing the side effect of bleeding time.

(Formulation Example) Formulation Example 1 Peptide of Acquisition Example 1 40 mg Purified gelatin 200 mg Sodium phosphate 79.6 mg Sodium chloride 163.6 mg Mannitol 100 mg The above components were dissolved in distilled water for injection to make a total volume of 10 mL.
After sterile filtration, fill 1.0 mL each in a sterile vial,
Lyophilization was performed to prepare a lyophilized composition.

Formulation Example 2 Peptide of Acquisition Example 1 20 mg Albumin 20 mg Sodium phosphate 34.8 mg Sodium chloride 81.8 mg Mannitol 25 mg The above components were weighed, and a lyophilized formulation was prepared in the same manner as in Formulation Example 1. Prepared.

Example 3 150 U / mg low molecular weight heparin 500,000 U Sodium chloride 4.5 g The above components were dissolved in distilled water for injection to make a total volume of 500 mL, sterile-filtered, and filled into 5.0-mL sterile vials. An ampoule having 5,000 U of active ingredient was prepared.

Formulation Example 4 Acquisition Example 1 produced in Example 1 in a packaging container having two pockets formed by blister molding a polypropylene sheet.
The vial containing the peptide and the ampoule containing the low-molecular-weight heparin prepared in Example 3 were respectively stored in pockets of the container, and a paper or plastic sheet having an aluminum foil laminated on the opening side of the container was heat-sealed. Thus, a package containing a combined amount of the peptide and heparin was obtained. This package was further housed in a paper package.

[0031]

EFFECT OF THE INVENTION According to the preventive / therapeutic agent for a disease associated with abnormal blood coagulation ability of the present invention, a disease associated with abnormal blood coagulation ability can be obtained by using a TM-like protein and heparin, or further using ATIII in combination. Especially deep vein thrombosis or DI
Compared with C, it is possible to enhance their prophylactic / therapeutic effects without increasing the bleeding tendency as compared to the administration of TM-like protein or heparin alone. In addition, heparin invalid cases, ATIII
Since it is expected to be effective for patients with reduced activity or patients with reduced protein C levels, it can be a clinically useful prophylactic / therapeutic agent. Also,
According to the prophylactic / therapeutic agent of the present invention, the combined use can reduce the dose of each drug. Therefore, the side effects observed when each drug is administered alone, in particular, bleeding due to heparin, shock, HIT and HITT
It is expected that the occurrence of side effects such as S can be suppressed, clinical safety is further improved, and usability is improved.

[Brief description of the drawings]

FIG. 1. Human normal plasma APT of TM-like protein and heparin
9 is a graph showing the effect on T.

FIG. 2 is a graph showing the effects of TM-like protein and low molecular weight heparin on human normal plasma APTT.

FIG. 3 is a graph showing the effects of TM-like protein and argatroban on human normal plasma APTT.

FIG. 4 is a graph showing the effects of TM-like protein and heparin on serum FDP in thromboplastin-induced DIC model rats.

FIG. 5 is a graph showing the effects of TM-like protein and heparin on APTT in thromboplastin-induced DIC model rats.

FIG. 6 is a graph showing the effects of TM-like protein and heparin on bleeding time in thromboplastin-induced DIC model rats.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Yoshitaka Hosaka 1-7 Yotsuya, Shinjuku-ku, Tokyo Mochida Pharmaceutical Co., Ltd. F-term (reference) 2G045 AA10 CA25 CA26 GC30 4C084 AA02 BA01 BA34 CA39 MA02 NA05 NA06 ZA541 4C086 AA01 EA27 MA02 MA03 NA05 NA06 ZA54

Claims (5)

[Claims] 1. A preventive / therapeutic agent for a disease associated with abnormal blood coagulation, characterized in that thrombomodulin-like protein and heparin are used in combination as active ingredients. 2. The preventive / therapeutic agent for a disease associated with abnormal blood coagulation ability according to claim 1, wherein antithrombin III is further used in combination. 3. The method according to claim 1, wherein the disease associated with abnormal blood coagulation ability is disseminated intravascular coagulation.
Therapeutic agent. 4. Administering a thrombomodulin-like protein,
2. The method according to claim 1, wherein heparin is administered thereafter.
4. The prophylactic / therapeutic agent according to any one of items 3 to 3. 5. The method according to claim 1, wherein heparin is administered, and thereafter, thrombomodulin-like protein is administered.
4. The prophylactic / therapeutic agent according to any one of items 3 to 3.