Urokinase (DB00013): A Comprehensive Pharmacological and Clinical Monograph

Foundational Characteristics and Molecular Profile

Identification and Nomenclature

Urokinase is a biotech therapeutic agent classified as a serine protease, known systematically as urokinase-type plasminogen activator (uPA).[1] It is a naturally occurring enzyme in humans and other animals, first discovered in 1947 by McFarlane and Pilling, though not named at that time.[1] As a therapeutic agent, it is identified by the DrugBank Accession Number DB00013 and the Chemical Abstracts Service (CAS) Number 9039-53-6.[1]

The drug is recognized under a variety of synonyms and international nonproprietary names, including Urokinasum (Latin) and Uroquinasa (Spanish).[3] Commercially, it has been marketed under brand names such as Kinlytic™, Abbokinase®, and Abbokinase® Open-Cath.[5] Other identifiers include Urinary Plasminogen Activator, Actosolv, Breokinase, and Ukidan.[3] For regulatory and classification purposes, it is assigned the Anatomical Therapeutic Chemical (ATC) code B01AD04 by the World Health Organization and the Unique Ingredient Identifier (UNII) 83G67E21XI.[1]

Physicochemical and Biochemical Properties

Urokinase is supplied for clinical use as a sterile, white or nearly white, amorphous, lyophilized powder.[7] As a protein-based therapy, its properties are defined by its complex biomolecular structure rather than a simple chemical formula.[4] The low molecular weight form of the protein, which is the principal active ingredient in therapeutic formulations like Kinlytic™, has an average molecular weight of approximately 31,126.5 Da and a chemical formula of

C1376​H2145​N383​O406​S18​.[4] It is important to note that some commercial preparations may contain a mixture of this low molecular weight form (approximately 33 kDa) and a high molecular weight form (approximately 54 kDa).[10]

A critical point of clarification arises from certain chemical databases that have erroneously associated the CAS number 9039-53-6 with small organic molecules, providing incorrect molecular formulas and IUPAC names.[7] This highlights a potential pitfall in automated data aggregation; the definitive identity of Urokinase (DB00013) is that of a large protein enzyme. This identity is confirmed by its complete 411-residue amino acid sequence and its classification as a biologic drug.[4]

Key biochemical properties that influence its behavior in physiological environments have been determined experimentally. The isoelectric point (pI) of Urokinase is 8.66, indicating it carries a net positive charge at physiological pH.[3] It has a measured melting point of 76 °C at a pH of 4.5 and a hydrophobicity value of -0.466, reflecting its relatively hydrophilic nature as a soluble plasma protein.[3] Its enzymatic activity is classified under EC 3.4.21.73 as a serine protease.[1]

Molecular Architecture: From Zymogen to Active Serine Protease

The sophisticated biological function of Urokinase is a direct consequence of its complex, multi-domain molecular architecture. In humans, the protein is encoded by the PLAU gene, which stands for "plasminogen activator, urokinase".[1]

Urokinase is synthesized as an inactive, single-chain zymogen known as prourokinase.[1] Activation is a critical proteolytic event, typically carried out by the enzyme plasmin, which cleaves a specific peptide bond between Lysine-158 (Lys158) and Isoleucine-159 (Ile159).[1] This cleavage converts the single-chain zymogen into the active, two-chain derivative, often referred to as high molecular weight uPA (HMW-uPA) or two-chain urokinase.[1] In this active conformation, the amino-terminal A-chain (consisting of residues 1-158) remains linked to the catalytically active, carboxy-terminal B-chain (residues 159-411) by a single sulfhydryl (disulfide) bond.[1] The low molecular weight form used in some therapies consists of the A chain (approximately 2 kDa) linked to the B chain (approximately 30.4 kDa).[8]

The 411-residue protein is organized into three distinct structural and functional domains, which are essential for its receptor binding and enzymatic activity [1]:

1. Epidermal Growth Factor (EGF)-like Domain (Residues 1-49): Located at the N-terminus, this domain is homologous to epidermal growth factor. Its primary function is to mediate high-affinity binding to the urokinase receptor (uPAR) on the cell surface, thereby localizing the enzyme's proteolytic activity.
2. Kringle Domain (Residues 50-131): This is a conserved, triple-loop protein structure stabilized by three internal disulfide bonds. Kringle domains are known to be involved in binding other proteins and are found in several proteins of the coagulation and fibrinolytic systems.
3. Serine Protease Domain (Residues 159-411): This C-terminal domain contains the catalytic triad (serine, histidine, and aspartate residues) characteristic of serine proteases. It is responsible for the enzymatic cleavage and activation of plasminogen.

A flexible interdomain linker, or "connecting peptide" (residues 132-158), connects the kringle domain to the protease domain.[1] This modular structure allows Urokinase to perform complex biological functions that extend beyond simple thrombolysis, including cell signaling and tissue remodeling, by tethering its powerful enzymatic activity to specific locations on cell surfaces.

Pharmacodynamics: The Mechanism of Fibrinolysis

The Plasminogen Activation Cascade

The primary therapeutic effect of Urokinase is achieved through its potent activity as a thrombolytic, or "clot-busting," agent.[6] It functions as a direct and specific enzyme within the endogenous fibrinolytic system.[9] The pharmacodynamic mechanism is centered on the activation of a critical proteolytic cascade.[1]

The primary physiological substrate for Urokinase is plasminogen, an inactive zymogen that circulates abundantly in the blood.[1] Urokinase, in its active two-chain form, functions as a serine protease that specifically cleaves the Arginine-560–Valine-561 (

Arg560−Val561) peptide bond within the plasminogen molecule.[3] This single proteolytic event converts plasminogen into its active form, the broad-spectrum serine protease plasmin.[1]

Once activated, plasmin acts as the principal effector enzyme of fibrinolysis. It systematically degrades the fibrin polymer mesh that forms the structural backbone of a thrombus (blood clot).[9] This process breaks the clot down into smaller, soluble fragments known as fibrin degradation products, ultimately leading to the dissolution of the thrombus and the restoration of blood flow.[17] In addition to fibrin, plasmin can also degrade fibrinogen and other plasma proteins involved in the coagulation cascade, such as Factors V and VIII.[9]

This direct mechanism of action is a key feature of Urokinase. Unlike tissue-type plasminogen activator (tPA), which is largely fibrin-dependent and shows significantly enhanced activity in the presence of a clot, Urokinase can activate plasminogen both systemically in the circulation and locally at the thrombus surface. This property contributes to a more generalized lytic state, which, while effective, can also increase the risk of systemic bleeding due to the degradation of circulating fibrinogen and other clotting factors.

Interaction with the Urokinase Receptor (uPAR) and Cell Surface Activity

Beyond its role as a circulating thrombolytic, Urokinase exerts highly localized and regulated effects through its interaction with a specific cell surface receptor. Urokinase binds with high affinity to the urokinase plasminogen activator surface receptor (uPAR), also known as CD87, which is expressed on various cell types, including endothelial cells, monocytes, and many cancer cells.[1]

This binding tethers the potent proteolytic activity of Urokinase to the cell membrane, concentrating its effect at the cell-extracellular matrix interface.[1] This localization is crucial for its physiological roles in processes that require controlled tissue breakdown, such as wound healing, angiogenesis (new blood vessel formation), and cell migration.[1]

Furthermore, the uPA/uPAR complex is not merely an anchor but a sophisticated signaling hub. Upon binding uPA, uPAR can interact with other membrane proteins, particularly integrins, and extracellular matrix components like vitronectin.[1] These interactions trigger intracellular signal transduction pathways that regulate cell adhesion, migration, proliferation, and survival.[1] This dual function—as both a protease localizer and a signaling modulator—underpins the broader biological significance of the uPA system, extending far beyond simple fibrinolysis. It is this same system that is often exploited by cancer cells to facilitate tissue invasion and metastasis, a pathological co-opting of a normal physiological process.[1]

Endogenous Regulation and Inhibition

In the physiological environment, the potent activity of Urokinase is tightly controlled to prevent unwanted proteolysis and bleeding. This regulation is primarily mediated by a class of proteins known as serine protease inhibitors, or serpins.[1]

The most important endogenous inhibitors of Urokinase are Plasminogen Activator Inhibitor-1 (PAI-1) and Plasminogen Activator Inhibitor-2 (PAI-2).[1] These serpins form a stable, covalent 1:1 complex with the active site of Urokinase, irreversibly inhibiting its enzymatic activity.[1] The balance between uPA and its inhibitors is a critical determinant of fibrinolytic homeostasis. An excess of PAI-1, for example, is associated with a prothrombotic state, while a deficiency can lead to a bleeding diathesis. When Urokinase is administered therapeutically in high doses, it overwhelms the capacity of these endogenous inhibitors, leading to a potent, systemic fibrinolytic state.

Pharmacokinetic Profile

The clinical administration, efficacy, and safety of Urokinase are directly governed by its pharmacokinetic properties, which are characteristic of a large protein therapeutic agent administered intravenously.

Absorption and Distribution

As a protein, Urokinase would be degraded in the gastrointestinal tract and therefore must be administered parenterally, typically via intravenous or intra-arterial infusion.[20] This ensures 100% bioavailability.[3]

Following intravenous administration, Urokinase distributes within the plasma and extracellular fluid. Its volume of distribution (Vd​) has been measured at approximately 11.5 L, a value consistent with a large molecule that does not extensively penetrate tissues and remains largely within the vascular and interstitial compartments.[3] The drug is rapidly cleared from the circulation, with most of the administered dose accumulating in the primary organs of metabolism and excretion: the liver and kidneys.[20]

Metabolism and Elimination

The clearance of Urokinase from the body is rapid and primarily hepatic. As a protein, it is catabolized by proteases into smaller, inactive peptides and constituent amino acids, which are then recycled or eliminated.[3] The liver is the main site of this metabolic clearance.[9]

Consequently, patients with significant hepatic impairment may exhibit reduced clearance of Urokinase. This can lead to a prolonged half-life and sustained elevation of fibrinolytic activity, thereby increasing the risk of bleeding complications.[9] Small fractions of the administered dose are also eliminated from the body through excretion in the bile and urine.[3]

Half-Life and Duration of Action

A defining pharmacokinetic feature of Urokinase is its very short biological half-life. The elimination half-life for its biologic activity is reported to be between 12.6 ± 6.2 minutes and 20 minutes.[3] This rapid clearance is the primary reason why sustained thrombolysis for conditions like massive pulmonary embolism requires a continuous intravenous infusion following an initial loading dose. A single bolus would be cleared from the circulation too quickly to dissolve a large, established thrombus. This pharmacokinetic reality directly dictates the standard 12-hour infusion protocol used in clinical practice.

Despite the rapid clearance of the drug itself, its pharmacodynamic effects are considerably more prolonged. The onset of action is immediate upon intravenous administration.[20] However, even after the infusion is discontinued and the drug is cleared from the plasma, the fibrinolytic state it induces persists. This is because Urokinase acts as a catalyst, generating large amounts of plasmin. This plasmin continues to circulate and exert its effects until it is neutralized by its own endogenous inhibitors (e.g.,

α2​-antiplasmin). As a result, laboratory markers of fibrinolysis, such as decreased plasma levels of fibrinogen and plasminogen and elevated levels of fibrin degradation products, can remain altered for 12 to 24 hours after the cessation of therapy.[9] This disconnect between the pharmacokinetic profile of the drug and the pharmacodynamic duration of its effect is of critical clinical importance, as the risk of hemorrhage persists long after the infusion has ended.

Clinical Pharmacology and Therapeutic Applications

Urokinase has been utilized in a range of thromboembolic disorders, with its indications evolving over time in response to clinical evidence and the availability of alternative agents.

Lysis of Acute Massive Pulmonary Embolism (PE)

The primary and most well-established indication for Urokinase is the lysis of acute massive pulmonary embolism.[5] Specifically, it is indicated for PE defined by the obstruction of blood flow to a pulmonary lobe or multiple lung segments, and particularly for cases accompanied by unstable hemodynamics, such as the failure to maintain blood pressure without supportive measures.[9] This was the sole indication for which the drug was re-approved by the U.S. Food and Drug Administration (FDA) in 2002.[24]

Clinical studies have shown that, compared to standard anticoagulation with heparin alone, Urokinase therapy leads to a more rapid improvement in angiographic findings, lung perfusion scans, and hemodynamic measurements within the first 24 hours of treatment.[9] To optimize efficacy, treatment should be initiated as soon as possible after the onset of symptoms.[9] Post-approval Phase 4 clinical trials have further explored its use, comparing the efficacy and safety of different infusion regimens, such as a shorter 2-hour infusion versus the standard 12-hour protocol.[25]

Management of Coronary Artery Thrombosis and Myocardial Infarction (MI)

Historically, Urokinase was a key therapeutic agent in the management of acute myocardial infarction caused by coronary artery thrombosis.[4] Its use was aimed at lysing the occlusive thrombus, restoring blood flow to the ischemic myocardium, improving left ventricular function, and reducing the risk of heart failure and death.[18]

For this indication, Urokinase was typically administered via intra-arterial infusion directly into the affected coronary artery during cardiac catheterization.[20] This catheter-directed approach allows for the delivery of a high concentration of the drug directly at the site of occlusion, potentially enhancing efficacy while minimizing systemic exposure. Clinical trials from that era compared Urokinase to other thrombolytics like streptokinase, demonstrating similar efficacy in recanalizing occluded arteries but with a more favorable safety profile for Urokinase, characterized by less systemic fibrinogenolysis and fewer bleeding complications.[28] It was also used effectively to treat acute intracoronary thrombus accumulation that can complicate percutaneous transluminal coronary angioplasty (PTCA) procedures.[29]

Restoration of Intravenous Catheter Patency (Catheter Clearance)

For many years, Urokinase was the standard of care and the only FDA-approved agent for restoring the patency of intravenous catheters, particularly central venous catheters, that have become occluded by fibrin or a blood clot.[1] This is a common complication in patients requiring long-term intravenous access for nutrition, dialysis, or medication administration.

The market withdrawal of Urokinase in 1999 created a significant clinical challenge and spurred the investigation of alternative thrombolytic agents for this off-label use.[30] This regulatory event was a primary catalyst for the widespread adoption and study of alteplase (tPA) for catheter clearance, ultimately leading to a shift in the standard of care.[30] Completed Phase 3 trials have also evaluated Urokinase, sometimes in combination with antimicrobial lock solutions like taurolidine, for the prevention of dialysis catheter malfunction.[33]

Other Investigated Thromboembolic Disorders

The application of Urokinase has been explored in several other thromboembolic conditions:

• Deep Vein Thrombosis (DVT): Urokinase is used in the treatment of DVT, often via catheter-directed thrombolysis (CDT).[5] This technique involves infusing the drug directly into the thrombus through a catheter, which may achieve more effective clot dissolution with a lower total drug dose and potentially less risk of systemic bleeding compared to systemic infusion.[34]
• Peripheral Arterial Occlusion: In some countries, such as Canada, Urokinase is indicated for the lysis of occlusive thromboemboli in peripheral arteries and arterial grafts.[4]
• Ischemic Stroke: The use of Urokinase for acute ischemic stroke has been investigated in clinical trials, with the goal of dissolving the cerebral artery occlusion and reducing subsequent neurological deficits.[18]

Dosage, Administration, and Reconstitution

The administration of Urokinase requires precise, indication-specific protocols and careful preparation to ensure both efficacy and safety. It should only be used by physicians experienced in managing thrombotic diseases in a hospital setting with adequate monitoring capabilities.[9]

Preparation and Reconstitution

Urokinase is supplied as a sterile, lyophilized powder in single-dose vials, commonly in a strength of 250,000 international units (IU).[6] The formulation contains excipients such as human albumin, mannitol, and sodium chloride.[9]

Reconstitution must be performed aseptically using Sterile Water for Injection, USP, without preservatives.[39] For a 250,000 IU vial, 5 mL of diluent is typically added to yield a final concentration of 50,000 IU/mL.[9] To prevent foaming and denaturation of the protein, the vial should not be shaken; instead, the diluent should be directed against the wall of the vial and the contents gently swirled until dissolved.[22] The resulting solution should be clear and slightly straw-colored.[9] For infusion, this reconstituted solution is further diluted in a compatible intravenous fluid, such as 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.[39]

Dosing and Administration Regimens

Dosage and administration route vary significantly depending on the clinical indication. The following table summarizes common protocols.

Indication	Route of Administration	Loading Dose	Maintenance / Instillation Dose	Key Administration Notes
Acute Massive Pulmonary Embolism	Intravenous (IV) Infusion	4,400 IU/kg over 10 minutes	4,400 IU/kg/hour for 12 hours	Administer via a programmable infusion pump. Follow therapy with anticoagulants once aPTT is <2x normal. 23
Coronary Artery Thrombosis	Intra-arterial (IA) Infusion	Not applicable	6,000 IU/minute via coronary catheter until reperfusion (typically 15-30 min). Average total dose ~500,000 IU.	Requires cardiac catheterization facilities. Monitor for reperfusion arrhythmias. 20
Peripheral Arterial Occlusion	Intra-arterial (IA) Infusion	2,000 units/kg (max 200,000 units)	2,000 units/kg/hr for 12 hours (max 200,000 units/hr)	Dosing is variable and determined by the interventional radiologist. Often used with concomitant heparin. 22
IV Catheter Occlusion	Intracatheter Instillation	Not applicable	Instill 5,000 IU to fill the catheter lumen.	Allow to dwell for 30-120 minutes before attempting aspiration. Dose may be repeated if necessary. 20

For systemic infusion in PE, a programmable pump is essential to accurately deliver the high-rate loading dose (e.g., at 90 mL/hr) and then switch to the lower-rate maintenance infusion (e.g., at 15 mL/hr).[39] After the infusion is complete, the line should be flushed with a compatible solution to ensure the entire dose is administered.[39] No other medications should be co-administered in the same intravenous line.[39]

Safety, Tolerability, and Risk Management

The potent therapeutic benefit of Urokinase is intrinsically linked to a significant risk of adverse events, primarily hemorrhagic complications. Safe use of the drug depends on meticulous patient selection and vigilant monitoring.

Hemorrhagic Complications: The Primary Clinical Risk

Bleeding is the most frequent and most serious adverse reaction associated with Urokinase therapy and can be fatal.[6] The risk is a direct extension of its mechanism of action, which induces a systemic lytic state. Bleeding can manifest in several ways:

• Superficial Bleeding: Oozing from catheter insertion sites, venipuncture sites, or surgical incisions; epistaxis (nosebleeds); and gingival bleeding are common.[6]
• Internal Bleeding: More serious internal hemorrhage can occur in the gastrointestinal tract (presenting as hematemesis or melena), genitourinary tract (hematuria), or retroperitoneal space.[6]
• Intracranial Hemorrhage (ICH): This is the most feared complication and can be life-threatening, presenting with symptoms such as sudden severe headache, confusion, focal neurological deficits, or decreased level of consciousness.[18]

During and after Urokinase administration, all invasive procedures should be minimized. Patients should be monitored closely for any signs of bleeding, and vital signs should be checked frequently.[23] While coagulation parameters like aPTT and fibrinogen levels are monitored, their values do not always correlate well with the clinical severity of bleeding.[9]

Non-Hemorrhagic Adverse Events

In addition to bleeding, other adverse events may occur:

• Infusion Reactions: Allergic-type and pyrogenic reactions are possible, including fever, chills, rigors, nausea, vomiting, and back pain.[9]
• Hypersensitivity and Anaphylaxis: Rare cases of severe, life-threatening anaphylaxis have been reported. Other hypersensitivity reactions can include bronchospasm, urticaria (hives), skin rash, and orolingual edema.[3]
• Cholesterol Embolization: This is a rare but serious systemic complication associated with all thrombolytic agents. It is believed to occur when the lytic process disrupts atherosclerotic plaques, releasing cholesterol crystals that embolize to distal organs, potentially causing renal failure, pancreatitis, or "purple toe" syndrome.[3]
• Cardiovascular Effects: Reperfusion of an occluded coronary artery can precipitate reperfusion arrhythmias. Transient hypotension or hypertension has also been observed.[18]

Contraindications and High-Risk Patient Populations

The critical importance of patient selection cannot be overstated. The decision to use Urokinase involves weighing the immediate life-threatening risk of the thromboembolic event against the significant risk of inducing a major hemorrhage.

Absolute Contraindications include conditions with an unacceptably high risk of bleeding [9]:

• Active internal bleeding
• History of cerebrovascular accident (stroke)
• Recent (within two months) intracranial or intraspinal surgery or serious head trauma
• Presence of an intracranial neoplasm, arteriovenous malformation, or aneurysm
• Severe uncontrolled hypertension

Relative Contraindications are conditions where the risk of bleeding is increased, and therapy should be considered with extreme caution [9]:

• Recent (within 10 days) major surgery, organ biopsy, obstetrical delivery, or serious trauma
• Recent serious gastrointestinal or genitourinary bleeding
• High likelihood of a left heart thrombus (e.g., mitral stenosis with atrial fibrillation)
• Bacterial endocarditis
• Diabetic hemorrhagic retinopathy
• Severe hepatic or renal dysfunction
• Pregnancy and the first 10 days postpartum

An additional safety consideration stems from its biological source. Therapeutic Urokinase is produced from human neonatal kidney cells grown in tissue culture or purified from human urine.[9] Although manufacturing processes include rigorous screening and viral clearance steps, products derived from human source material carry a remote theoretical risk of transmitting infectious agents.[9] It was, in fact, concerns over the adequacy of these manufacturing controls that led to its temporary market withdrawal in 1999.[24]

Black Box Warning Status

The provided documentation does not indicate that Urokinase carries a formal "Black Box Warning" from the FDA. While the risks associated with its use, particularly hemorrhage, are severe and prominently featured in its labeling, it does not appear to have been assigned this specific highest-level warning.[44]

Drug and Substance Interactions

The risk of bleeding with Urokinase is significantly amplified when it is used concomitantly with other drugs that affect hemostasis. These interactions are of major clinical significance and often necessitate avoidance of the combination.

Interactions with Anticoagulants and Antiplatelet Agents

The most critical interactions involve other antithrombotic agents. The concurrent use of Urokinase with drugs that inhibit the coagulation cascade or platelet function results in a synergistic effect on hemostasis, dramatically increasing the risk of severe and life-threatening hemorrhage.[9]

• Anticoagulants: This class includes heparin, low molecular weight heparins (e.g., enoxaparin), warfarin (Coumadin), and direct oral anticoagulants (DOACs) such as apixaban, rivaroxaban, and dabigatran. Heparin therapy should be discontinued before initiating Urokinase infusion.[4]
• Antiplatelet Agents: This category includes aspirin, P2Y12 inhibitors (e.g., clopidogrel), dipyridamole, and potent intravenous glycoprotein IIb/IIIa inhibitors (e.g., abciximab, eptifibatide).[4] Patients are typically advised to avoid taking aspirin and other antiplatelet drugs shortly after receiving Urokinase.[6]

Other Clinically Significant Interactions

The following table summarizes key drug interactions with Urokinase, categorized by their clinical effect and severity.

Interacting Drug Class/Agent	Example Drugs	Potential Effect	Severity / Recommendation
Anticoagulants	Warfarin, Heparin, Apixaban, Rivaroxaban	Synergistically increased risk of severe hemorrhage.	Major: Avoid combination. Discontinue anticoagulant before starting Urokinase. 4
Antiplatelet Agents	Aspirin, Clopidogrel, Dipyridamole, Abciximab	Synergistically increased risk of severe hemorrhage.	Major: Avoid combination. 4
NSAIDs	Ibuprofen, Naproxen, Diclofenac, Ketorolac	Increased risk of bleeding due to antiplatelet effects and potential for GI ulceration.	Major: Avoid combination. 4
Other Thrombolytics	Alteplase, Reteplase, Streptokinase	Synergistically increased risk of severe hemorrhage.	Major: Avoid combination. 4
Antifibrinolytic Agents	Aminocaproic acid, Tranexamic acid	Directly antagonize the thrombolytic effect of Urokinase, decreasing its efficacy.	Major: Avoid combination. Used as an antidote for overdose. 4
ACE Inhibitors	Lisinopril, Enalapril, Ramipril	Increased risk of angioedema.	Moderate: Use with caution and monitor for signs of angioedema. 4
Herbal Supplements	Garlic, Ginger, Ginkgo biloba	May have antiplatelet/anticoagulant properties, increasing bleeding risk.	Moderate: Usually avoid combinations; use only under special circumstances. 51
Alcohol	Ethanol	Increases the risk of bleeding.	Moderate: Avoid during and immediately after therapy. 48

Regulatory and Commercial Landscape

The regulatory and commercial history of Urokinase in the United States is unique and serves as an important case study in the manufacturing challenges of biologic drugs and their impact on clinical practice and market dynamics.

FDA Approval History: A Timeline

• January 16, 1978: Urokinase was first granted approval by the U.S. FDA, becoming a foundational therapy for thromboembolic diseases.[3]
• December 1998 – January 1999: The drug was taken off the market. This was not due to issues with its clinical efficacy or safety profile but because of significant manufacturing concerns.[24] FDA inspections of the manufacturing facility of Abbott Laboratories revealed deviations from Current Good Manufacturing Practice (cGMP) regulations. The primary concern was the potential for transmission of infectious agents from the human neonatal kidney cell source material due to inadequate testing and contamination prevention measures.[24]
• October 11, 2002: After a four-year absence, during which Abbott invested in upgrading its manufacturing facilities and implementing more rigorous controls and testing, the FDA re-approved Urokinase (Abbokinase®).[24] However, this re-approval was for a single, limited indication: the lysis of acute massive pulmonary embolism. The previous indications for coronary artery thrombosis and catheter clearance were not included, as the company focused on the PE indication to expedite its return to the market.[24]
• Post-2010 Discontinuation: By October 2010, Urokinase was noted as being unavailable in the United States.[53] The official FDA Purple Book, which lists licensed biological products, now lists the marketing status for all strengths of Kinlytic™ (urokinase) as "Discontinued".[3]

Brand Names and Formulations

Throughout its time on the market, Urokinase was sold under several brand names, most notably Kinlytic™ and Abbokinase®.[5] It was formulated as a powder for injection in single-dose vials of varying strengths, including 5,000 IU, 9,000 IU, and 250,000 IU, all of which are now discontinued in the U.S..[6]

Current Global Status and Availability

While no longer marketed in the U.S., Urokinase continues to be an important therapeutic agent in other parts of the world. It remains in use in some European countries and is a dominant thrombolytic agent in China, particularly for catheter-directed thrombolysis in conditions like DVT.[34] In regions where it is not commercially registered, such as Australia, it may be available through special access schemes for specific patients.[22]

The four-year absence of Urokinase from the U.S. market had a lasting impact on clinical practice. It created a therapeutic vacuum, especially for catheter clearance, that accelerated the adoption and study of rival thrombolytics like the recombinant tissue plasminogen activators alteplase (Activase®) and reteplase (Retevase®).[24] By the time Urokinase returned with a limited indication, these alternative agents had become firmly established, altering the market landscape and likely contributing to its eventual commercial discontinuation in the U.S.

Broader Biological Roles and Future Perspectives

The clinical story of Urokinase as a therapeutic agent is only one part of the broader biological significance of the urokinase-type plasminogen activator (uPA) system. This system is a fundamental regulator of extracellular proteolysis, playing critical roles in both normal physiology and complex pathologies like cancer.

The Urokinase System in Cancer Progression and Metastasis

One of the most intensely studied areas of uPA biology is its role in cancer. A substantial body of evidence has established a strong correlation between the elevated expression of uPA and its receptor, uPAR, and tumor malignancy, aggressive progression, and poor prognosis in numerous cancers, particularly breast cancer.[1]

The uPA system is a key facilitator of tumor invasion and metastasis through several mechanisms:

• Extracellular Matrix (ECM) Degradation: When expressed on the surface of cancer cells, the uPA/uPAR complex activates plasminogen to plasmin. Plasmin directly degrades components of the ECM and also activates other proteases, such as matrix metalloproteinases (MMPs). This concerted proteolytic activity breaks down the tissue barriers of the basement membrane and surrounding stroma, clearing a path for cancer cells to invade local tissues and enter the bloodstream or lymphatic system.[1]
• Angiogenesis: The growth of tumors beyond a small size requires the formation of new blood vessels, a process known as angiogenesis. The breakdown of the ECM by the uPA system is a crucial initiating step in this process.[1]
• Cell Signaling: Beyond its enzymatic function, the uPA/uPAR system acts as a signaling complex that influences cancer cell adhesion, migration, and proliferation, further contributing to the metastatic phenotype.[1]

Urokinase as a Biomarker and Therapeutic Target in Oncology

Given its causal role in cancer progression, the uPA system has emerged as a valuable biomarker and a compelling therapeutic target. Levels of uPA and its inhibitor, PAI-1, in primary breast tumor tissue are among the strongest prognostic factors for disease recurrence, and their measurement can help guide decisions about adjuvant chemotherapy.[1]

This understanding has led to a fascinating therapeutic paradox. While Urokinase is administered as a drug to promote proteolysis for thrombolysis, the goal in oncology is to inhibit the endogenous uPA system to prevent the proteolysis that drives metastasis. This has spurred the development of specific inhibitors targeting uPA's enzymatic activity or its interaction with uPAR. Agents such as upamostat have been investigated as potential anti-cancer drugs, representing a shift in focus from using Urokinase as a tool to targeting it as a culprit.[1]

Physiological Roles in Tissue Remodeling

The pathological roles of the uPA system in cancer are an aberrant manifestation of its essential physiological functions. In healthy tissues, the same processes of controlled ECM degradation and cell migration are vital for a variety of processes, including embryogenesis, ovulation, and, most notably, wound healing, where it facilitates the migration of keratinocytes and other cells to repair damaged tissue.[1]

Conclusion

Urokinase (DB00013) is a serine protease with a rich and complex history as a therapeutic agent. Its elegant molecular mechanism, involving the direct activation of plasminogen to the fibrin-degrading enzyme plasmin, established it as a potent thrombolytic for life-threatening conditions such as acute massive pulmonary embolism and coronary artery thrombosis. Its pharmacokinetic profile, characterized by a very short half-life, necessitated continuous infusion protocols to maintain a therapeutic effect, while its pharmacodynamic consequences persisted long after the drug's clearance, underscoring the need for vigilant clinical monitoring.

The regulatory journey of Urokinase in the United States—from its initial approval in 1978, to its market withdrawal in 1999 due to manufacturing concerns, its limited re-approval in 2002, and its eventual discontinuation—serves as a powerful case study on the unique challenges of producing biologic drugs from human sources and the profound impact that supply chain disruptions can have on clinical practice and market dynamics.

Beyond its role as a therapeutic agent, the urokinase-type plasminogen activator system is now recognized as a fundamental modulator of cell-matrix interactions with a dual nature. It is essential for physiological tissue remodeling but is also pathologically co-opted by cancer cells to drive invasion and metastasis. This has positioned the uPA system as a critical prognostic biomarker and an attractive therapeutic target in oncology. Therefore, while the chapter on Urokinase as an administered thrombolytic may be closing in some parts of the world, the scientific and medical story of uPA as a central player in health and disease continues to evolve, with future therapeutic strategies likely to focus on its inhibition rather than its administration.

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