Abstract: A method of treatment for human patients with an acquired hypercoagulable state or acquired protein C deficiency associated with sepsis, purpura fulminans, meningococcal sepsis, bone marrow and other transplantations, severe burns, pregnancy, major surgery, severe trauma, or ARDS, which comprises administering activated protein C providing a highly selective therapeutic agent with a low potential for causing bleeding complications.

Abstract: The invention provides compositions comprising microspheres of fibrinogen-coated cross-linked albumin microspheres having a size range of primarily from about 100 to about 5000 nanometers diameter, wherein the composition is substantially free microspheres and microsphere aggregates having a diameter of more than 10 micrometers. At least a portion of the fibrinogen on the surface of the microspheres is covalently attached. The particles of the invention are useful for reducing bleeding time when administered to a human or other animal.

Abstract: The subject invention relates to fibrin sealants. More specifically, the subject invention relates to the use of a fibrin sealant wherein a composition comprising fibrin monomer or a composition comprising noncrosslinked fibrin is utilized as a component of the fibrin sealant.

Abstract: An adhesive for tissue capable of uniformly forming a high concentration of fibrin so as to provide a high closing effect is disclosed. The adhesive for tissue comprises a fibrinogen solution and a thrombin solution which solutions are separated from each other. The adhesive is to be mixed and spray coated together with a sterile gas and has a volume ratio of the fibrinogen solution to the thrombin solution of about 2:1 to 10:1. This adhesive is to be sprayed together with a sterile gas for the adhesion or closing of living tissue of a human being or animal.

Abstract: A process for the preparation of a concentrate of von Willebrand factor is described, entailing a solution of a complex of this factor with factor VIII:C being optionally pasteurized and treated with an anion exchanger, there being no binding of the von Willebrand factor.

Abstract: The present invention provides an antibody which specifically reacts with an epitope of a polypeptide comprising the amino acid sequence X-Y-CYS GLN GLU GLU GLU CYS PRO ASP PRO TYR LEU CYS SER PRO VAL THR ASN ARG CYS GLU CYS THR PRO VAL LEU CYS ARG MET TYR CYS LYS PHE TRP ALA LYS ASP GLU LYS GLY CYS GLU ILE CYS LYS CYS GLU GLU LEU CYS GLN ASN GLN ASN CYS THR LYS ASP MET LEU CYS SER SER VAL THR ASN ARG CYS ASP CYS GLN ASP PHE LYS CYS PRO GLN SER TYR CYS-Z (SEQ. ID NO. 1) wherein X is MET or absent; Y is 0-28 amino acids of the sequence LYS MET CYS TRP ASN LYS GLY CYS PRO CYS GLY GLN ARG CYS ASN LEU HIS ARG ASN GLU CYS GLU VAL ILE ALA GLU ASN ILE GLU, (SEQ. ID NO. 2) with the proviso that if part of the sequence is present, it is a carboxy-terminal part of the sequence including the carboxy-terminal GLU and wherein Val may be preceded by Gly; and Z is absent or all or a part of the sequence Pro110-Lys156 shown in FIG. 7 (SEQ. ID NO.

Abstract: This invention provides methods for the localized delivery of supplemented tissue sealants, wherein the supplemented tissue sealants comprise at least one composition which is selected from one or more antibodies, analgesics, anticoagulants, anti-inflammatory compounds, antimicrobial compositions, antiproliferatives, cytokines, cytotoxins, drugs, growth factors, interferons, hormones, lipids, demineralized bone or bone morphogenetic proteins, cartilage inducing factors, oligonucleotides polymers, polysaccharides, polypeptides, protease inhibitors, vasoconstrictors or vasodilators, vitamins, minerals, stabilizers and the like. Further provided are methods of using the site-specific supplemented tissue sealants, including preparation of a biomaterial.

Abstract: The invention provides a method of disaggregating a ligand:integrin receptor complex. Specifically, the invention provides a method of disaggregating an existing platelet thrombus in a blood vessel in a subject, comprising administering to the subject a compound which dissociates fibrinogen bound to a first site on platelet glycoprotein IIB-IIIa, by binding a second interacting site on the platelet glycoprotein IIB-IIIa, thereby disaggregating the platelet thrombus. The present invention also provides a method of screening compounds for the ability to dissociate a ligand from its integrin receptor by binding an interacting second site, comprising contacting the compound with an existing ligand:integrin receptor complex and determining if the complex dissociates.

Abstract: There is provided the use of a thrombin inhibitor in the manufacture of a product for use in the control of wound healing processes within the body, in particular, the inhibition or prevention of fibrin-related adhesion and/or scar tissue formation, as well as products for use in the control of wound healing processes within the body comprising polysaccharides (e.g., chitosans) and low molecular weight peptide-based thrombin inhibitors.

Abstract: A method of treatment for human patients with an acquired hypercoagulable state or acquired protein C deficiency associated with sepsis, purpura fulminans, meningococcal sepsis, bone marrow and other transplantations, severe burns, pregnancy, major surgery, severe trauma, or ARDS, which comprises administering activated protein C providing a highly selective therapeutic agent with a low potential for causing bleeding complications.

Abstract: The present invention provides fibrin microbeads that are biologically active and comprise extensively cross-linked fibrin(ogen) without using glutaraldehyde, and a method for preparing the fibrin microbeads. The present invention also provides a composition comprising cells bound to the fibrin microbeads, and methods for culturing and separating cells using the fibrin microbeads of the present invention. Finally, the present invention provides methods for transplanting cells and engineering tissue using the fibrin microbeads of the present invention.

Abstract: A method and device for activating and applying a solution of fibrinogen to form fibrin glue at a desired site. The method includes contacting the solution of fibrinogen with immobilized thrombin under conditions that result in a solution of polymerizable fibrin and delivering the activated solution to the desired site. The device includes a housing having a compartment for a solution of fibrinogen, a container for immobilized thrombin, a structure following the solution of fibrinogen to be brought into contact with the immobilized thrombin under conditions which permit the activation of the fibrinogen to polymerizable fibrin, and a structure allowing for delivery of the activated solution to the desired site.

Abstract: A process for determining glycosaminoglycans in antithrombin III (ATIII)-containing solutions by increasing the ionic strength of the AT III-containing solution until the interaction between AT III and glycosaminoglycans is prevented, removing the AT III which has been released from the glycosaminoglycans from the solution, and desalting and determining the glycosaminoglycan which has remained in the solution.

Abstract: This invention provides supplemented tissue sealants, methods for their production and use thereof. Disclosed are tissue sealants supplemented with at least one cytotoxin or cell proliferation inhibiting composition. The composition may be further supplemented with, for example, one or more antibodies, analgesics, anticoagulants, anti-inflammatory compounds, antimicrobial compositions, cytokines, drugs, growth factors, interferons, hormones, lipids, demineralized bone or bone morphogenetic proteins, cartilage inducing factors, oligonucleotides polymers, polysaccharides, polypeptides, protease inhibitors, vasoconstrictors or vasodilators, vitamins, minerals, stabilizers and the like.

Abstract: The present invention provides methods and compositions relating to synthetic test stains comprising isolated fibrin and/or fibrin precursors and blood plasma proteins. Kits for the preparation of synthetic test stains containing an isolated fibrin precursor and an initiator for converting the fibrin precursor to fibrin are also provided. In addition, methods for checking the efficiency of cleaning processes, and kits for carrying out these methods are provided.

Abstract: The present invention relates to thrombin-containing hemostatic compositions, their preparation and use. In particular, it relates to hemostatic compositions comprising stabilized thrombin and microfibrillar collagen in an aqueous medium. In a preferred embodiment of the present invention, the compositions are used in a kit comprising two different components, one of which is autologous patient's plasma as the source of fibrinogen, and the other of which is the thrombin-containing composition which also contains microfibrillar collagen having an average diameter of about 3-30 nanometers.

Abstract: This invention relates generally to apparatuses and processes for preparing fibrinogen glue from autologous plasma. More particularly, this invention relates to a novel apparatus comprising a plasma membrane separator to extract and separate the autologous plasma from other undesirable compositions in the blood. The autologous plasma is transferred to a membrane separator to provide separation of the fibrinogen from other compositions with a desirable amount of ether or other suitable solvents containing an-OH group in the presence of a mixing means. The fibrinogen so separated is transferred to a fibrinogen collector which is connected to a vacuum pump through a sterile filter to remove the ether or other suitable solvents contained thereof. A freezer is provided to maintain the autologous plasma in the membrane separator and the fibrinogen in the fibrinogen collector at a desirable temperature.

Abstract: A stabilized aqueous liquid preparation of human blood coagulation factor XIII, prepared by recombinant DNA technology, from the group consisting of galactose, sucrose, sorbitol, glutamate, aspartate and histidine and where little reduction in biological activity occurs even when stored for a longer time.

Abstract: The invention is directed to fibrin materials for use in fibrin compositions and methods that avoid the need to use thrombin as an activating agent for fibrin monomer-based sealants. The invention provides for substantially pure fibrin chains, fibrin chain precursors, fibrin chains with other N-terminal extensions, fibrin monomer, fibrin-homolog and fibrin-analog. The invention further provides for variant fibrin .gamma.-chains. The variant gamma-chain contains one or more mutations and/or deletions in the C-terminal region following the coiled-coil forming region such that, when incorporated into fibrin-homolog, the homolog lacks the ability to self-polymerize but has the ability to form non-covalent bonds, and thereby form mixed polymers useful as sealants, with fibrinogen. The invention also provides nucleotide sequences encoding fibrin chains or fibrin chain variants and cells expressing fibrin chains, fibrin chain variants, fibrin monomer, fibrin precursor or fibrinogen-analog.

Abstract: A device for producing fibrinogen includes a platen having a surface configured for heat exchange with a container, which is adhered to the platen by device of a vacuum and heat exchange allowing both cooling and heating to occur along the boundary between the container and the platen. The platen is operatively coupled to a device of rocking the platen about a horizontal axis and the container allows scavenging of a cryoprecipitate fibrinogen from the blood product for subsequent utilization.

Abstract: The subject invention relates to fibrin sealants. More specifically, the subject invention relates to the use of a fibrin sealant wherein a composition comprising fibrin monomer or a composition comprising noncrosslinked fibrin is utilized as a component of the fibrin sealant.

Abstract: An assay method that requires a soluble fibrin monomer or a soluble fibrin monomer reagent as one of the components of the assay. The reagent is a fibrin-like material having a solubility and stability similar to fibrinogen in that it remains soluble and stable at physiological conditions at a concentration employed in the assay in the absence of fibrin polymerization inhibitors or reagents for maintaining solubility.

Abstract: Solid, fibrous bioabsorbable hemostatic compositions containing a bioabsorbable polymer and a hemostatic compound, methods for making the hemostatic compositions, and methods for using the hemostatic compositions are disclosed.

Abstract: This invention provides a fibrin sealant dressing, wherein said fibrin sealant may be supplemented with at least one composition selected from, for example, one or more regulatory compounds, antibody, antimicrobial compositions, analgesics, anticoagulants, antiproliferatives, anti-inflammatory compounds, cytokines, cytotoxins, drugs, growth factors, interferons, hormones, lipids, demineralized bone or bone morphogenetic proteins, cartilage inducing factors, oligonucleotides polymers, polysaccharides, polypeptides, protease inhibitors, vasoconstrictors or vasodilators, vitamins, minerals, stabilizers and the like. Also disclosed are methods of preparing and/or using the unsupplemented or supplemented fibrin sealant dressing.

Abstract: A method for the determination of soluble fibrin in a body fluid of a species is described, entailing use of a binding partner which is bound to a solid phase, and of a labeled bioaffinity binding partner, for fibrin.

Abstract: The subject invention relates to fibrin sealants. More specifically, the subject invention relates to the use of a fibrin sealant wherein a composition comprising fibrin monomer or a composition comprising noncrosslinked fibrin is utilized as a component of the fibrin sealant.

Abstract: Compositions and methods for avidin immobilized on an inert support material, e.g. agarose, are disclosed. The compositions have high activity levels of avidin and may further include a bulking agent, e.g., maltose, and a protectant to maintain the stability and integrity of the avidin agarose during lyophilization and terminal sterilization processes. These compositions have applicability in any instance where avidin agarose and/or the avidin/biotin technology are useful. In particular, the present compositions are useful in an enzyme capture system to prepare fibrin monomer useful for fibrin sealants. The fibrin is prepared by subjecting a fibrinogen-containing composition to a biotinylated enzyme to convert the fibrinogen in the composition to a corresponding fibrin monomer. A fibrin monomer/biotinylated enzyme mixture is formed.

Abstract: The present invention provides methods of producing recombinant fibrinogen in a long-term mammalian cell culture system. Disclosed is a method for the production of recombinant fibrinogen, comprising: growing mammalian cells that express recombinant fibrinogen in a serum-free medium for a time of at least one month at a level of at least 5 .mu.g/ml; and then collecting portions of the conditioned medium at least twice during the culturing time of at least one month, with each portion containing at least 5 .mu.g/ml of recombinant fibrinogen. Also disclosed is a method for the production of recombinant fibrinogen, comprising: growing mammalian cells that express recombinant fibrinogen in a serum-free medium at a level greater than 1 .mu.g/ml; collecting at least a portion of the conditioned medium, and then purifying the fibrinogen from the medium by anion-exchange chromatography or affinity chromatography.

Abstract: Assays employing fibronectin-depleted substrates are described to identify invasion inducing agents. Such agents are useful for in vivo wound healing, including but not limited to deep wounds and chronic wounds.

Abstract: The invention relates to a method for the renaturation of denatured proteins in which they are treated with a renaturant which has on vicinal carbon atoms a hydroxyl group and at least one fluorine atom.

Abstract: A two-component fibrin glue for human application includes a) a component A containing i) a virus-inactivated and concentrated cryoprecipitate that contains fibrinogen, and ii) tranexamic acid or a pharmaceutically acceptable salt, thereof; and b) component B containing a proteolytic enzyme that, upon combination with component A, cleaves, specifically, fibrinogen present in the cryoprecipitate of component A, thereby, effecting a fibrin polymer.

Abstract: The invention provides vitamin k-dependent polypeptides with enhanced membrane binding affinity. These polypeptides can be used to modulate clot formation in mammals. Methods of modulating clot formation in mammals are also described.

Abstract: A method of treatment for human patients with an acquired hypercoagulable state or acquired protein C deficiency associated with sepsis, purpura fulminans, meningococcal sepsis, bone marrow and other transplantations, severe burns, pregnancy, major surgery, severe trauma, or ARDS, which comprises administering activated protein C providing a highly selective therapeutic agent with a low potential for causing bleeding complications.

Abstract: The present invention is a fibrin sealant and a method for producing a fibrin sealant from fish blood. Whole blood is drawn from the donor fish and centifuged to separate blood cells from plasma. Prothrombin and fibrinogen are extracted from this plasma, and the prothrombin is activated to thrombin. The fibrinogen and thrombin components are then combined as needed to form the fibrin sealant.

Abstract: Conjugates having a clinically useful delivery vehicle linked to a biologically active species which acts to increase vascular permeability and expand blood volume at or in proximity to the tumor site are disclosed. The vehicle-linked species may be, for example, a vasoactive agent, a substance that recruits or amplifies a vasoactive species, a drug, or a pharmaceutical compound. Suitable biological species comprises peptides, lipids, carbohydrates, or their derivatives. Chemical or recombinant DNA methods suitable for linking the species to the vehicles are indicated. A therapy is disclosed which comprises administering the vasoactive conjugate and delivering a diagnostic agent or a therapeutic agent at an optimal time thereafter, when tumor vasculature is maximally affected.

Abstract: Disclosed are various compositions and methods for use in achieving specific blood coagulation. This is exemplified by the specific in vivo coagulation of tumor vasculature, causing tumor regression, through the site-specific delivery of a coagulant using a bispecific antibody.

Abstract: A thrombin inhibitor is disclosed. The thrombin inhibitor comprises: (1) a segment which inactivates or sequesters thrombin; (2) a segment comprising a portion of the fibrinogen .gamma.' chain that binds to the thrombin exosite, such as amino acid residues (414-427) and amino acid residues (414-425) of the native human fibrinogen .gamma.' sequence.

Abstract: The present invention is directed to the generation of antibodies which preferentially bind to fibrinogen fragments E1, E2, and E3, but exhibit little or no cross-reactivity against fibrin monomer and fibrinogen. Thus, the invention provides synthetic peptides containing defined amino acid sequences corresponding to the carboxy terminal regions of the E fragments which arise as a result of plasmin cleavage of fibrin and fibrinogen. The synthetic peptides may be synthesized chemically, or through genetic manipulations, and may contain additional amino acid sequences which are not contiguous with the defined E fragment sequences.

Abstract: An adhesive for tissue capable of uniformly forming a high concentration of fibrin so as to provide a high closing effect is disclosed. The adhesive for tissue comprises a fibrinogen solution and a thrombin solution which solutions are separated from each other. The adhesive is to be mixed and spray coated together with a sterile gas and has a volume ratio of the fibrinogen solution to the thrombin solution of about 2:1 to 10:1. This adhesive is to be sprayed together with a sterile gas for the adhesion or closing of living tissue of a human being or animal.

Abstract: Platelet substitutes, comprising fibrinogen, or analogous products useful in therapy, which further comprise an insoluble carrier to which is bound an essentially non-degraded active protein including the sequence Arg-Gly-Asp. Such conjugates can be made by a conjugation process comprising 0.01 to 2.5% by weight active fibrinogen, and no more that 50% inactive fibrinogen.

Abstract: The invention relates to storage-stable fibrinogen preparations for preparing concentrated fibrinogen solution for use as a tissue adhesive or for preparing fibrinogen solutions for other uses, for example, for infusion purposes. The fibrinogen preparations are characterized in that(i) the lyophilized preparation comprises a substance improving the solubility of fibrinogen such that the reconstitution time is up to 15 minutes, preferably less than 7 minutes, when dissolving with water at room temperature to a solution with a fibrinogen concentration of at least 70 mg/ml and(ii) the ready-to-use tissue adhesive solution obtained from the preparation forms fibrin clots having physiological fibrin structure after mixing with a thrombin-CaCl.sub.2 solution.

Abstract: The subject invention relates to fibrin sealants. More specifically, the subject invention relates to the use of a fibrin sealant wherein a composition comprising fibrin monomer or a composition comprising noncrosslinked fibrin is utilized as a component of the fibrin sealant.

Abstract: This invention is directed to solid compositions, for example, lyophilized forms, of fibrin monomer. These compositions are useful wherever fibrin monomer could be employed, e.g., as a surgical sealant to provide hemostasis.

Abstract: The present invention provides a method for screening candidate agents to identify compounds that modulate the hemostatic system. The method of the invention involves a screening medium comprised of stored whole blood, preferably diluted with buffer, to which unrefrigerated platelets have been added. Candidate agents that may inhibit or activate clot formation or clot lysis are added to the screening medium and suitable compounds are identified. The assay provided is physiologically relevant, rapid, inexpensive and allows for large scale screening of candidate agents.

Abstract: This invention relates to radiolabeled reagents that are scintigraphic imaging agents for imaging sites of thrombus formation in vivo, and methods for producing such reagents. Specifically, the invention relates to reagents each comprised of a specific binding compound, capable of binding to at least one component of a thrombus, covalently linked to a radiolabel-binding moiety. The invention provides these reagents, methods and kits for making such reagents, and methods for using such reagents labeled with technetium-99m to image thrombus sites in a mammalian body.

Abstract: The present invention contemplates therapeutic compositions containing a fibrinogen homolog capable of binding to endothelial cells in an RGD-independent manner that inhibits fibrinogen binding to endothelial cells. Also described are therapeutic compositions containing an ICAM-1 homolog capable of binding to fibrinogen in an RGD-independent manner that inhibits fibrinogen binding to endothelial cells. Methods of inhibiting endothelial cell and fibrinogen mediated inflammation within a patient by administering a homolog of this invention are also contemplated.

Abstract: A process for the preparation of factor IX from a biological source by chromatography involves prior treatment with ammonium sulfate as a protein precipitant at a concentration of from 1.5-2.3 mol/l.

Abstract: This invention provides an imaging agent which comprises a polypeptide labeled with an imageable marker, such polypeptide having an amino acid sequence substantially present in the fibrin binding domain of naturally-occurring human fibronectin and being capable of binding to fibrin. The invention further provides a method wherein the imaging agent is used for imaging a fibrin-containing substance, i.e., a thrombus or atherosclerotic plaque. Further provided are plasmids for expression of polypeptides having an amino acid sequence substantially present in the fibrin binding domain of naturally-occurring human fibronectin and being capable of binding to fibrin, hosts containing these plasmids, methods of producing the polypeptides, methods of treatment using the polypeptides, and methods of recovering, refolding and reoxidizing the polypeptides.

Abstract: A clot lysis time determining device for determining the time necessary for fluid to lyse a clot. The device comprises: a body defining a chamber; a fluid receiving inlet port to the body in fluid communication with the chamber, the inlet port permitting fluid to flow into the chamber; a fluid discharging outlet port to the body in fluid communication with the chamber, the outlet port permitting fluid to flow out from the chamber; the inlet port, chamber, and outlet port defining a communicating fluid passageway; a body opening formed in the body along the fluid passageway, the body opening permitting a portion of fluid to flow against a clot supported by clot-supporting porous membrane; and a membrane cover detachably connectable to the body and configured for holding a clot-supporting porous membrane over the body opening.

Abstract: A method and device for activating and applying a solution of fibrinogen to a desired site. The method includes contacting the solution of fibrinogen with immobilized thrombin resulting in an activated solution of polymerizable fibrin, and delivering the activated solution to the desired site. The device includes a housing having a compartment for a solution of fibrinogen, immobilized thrombin, a structure for bringing the solution of fibrinogen in contact with the immobilized thrombin under conditions which permit the activation of the fibrinogen resulting in polymerizable fibrin, and a structure for delivery of the activated solution to the desired site.