ReviewFibrinolysis and the control of blood coagulation
Introduction
Platelets are activated upon contact with subendothelial matrix proteins, including collagen, von Willebrand factor, and fibronectin, in response to vascular injury [1]. Platelet activation leads to exposure of cell surface anionic phospholipids, which serve as a nidus for the assembly of procoagulant proteins. In the ensuing activation of the coagulation cascade, a sequential series of serine protease-mediated cleavage events, thrombin is activated from its zymogen prothrombin [2]. Active thrombin can then catalyze the polymerization of fibrin by cleaving small peptides from two of its three subunits. Polymerization converts soluble fibrinogen into insoluble fibrin, which stems the flow of blood, thus achieving “hemostasis,” the prevention of major blood loss [3]. As the clot or “thrombus” forms, circulating red blood cells, white blood cells, and platelets become incorporated into its structure. In addition, fibrin becomes cross-linked through the action of factor XIIIa, which is also activated by thrombin, and provides further structural stability [4]. Upon healing of the injured blood vessel, the effete thrombus is lysed through the action of plasmin. Plasmin is generated from the zymogen plasminogen on the surface of the fibrin clot, or on cell surfaces, by either tissue plasminogen activator (tPA) or urokinase (uPA) [5]. Proteolysis of fibrin gives rise to soluble fibrin degradation products (FDPs), some of which have immunomodulatory and chemotactic functions. The coagulation and fibrinolytic systems are highly regulated and inter-related through mechanisms that insure balanced hemostasis.
Section snippets
Fibrin formation and clot structure
Fibrinogen, a soluble 340-kDa protein, circulates in whole blood at concentrations of 2–4 mg/mL [6]. It consists of two sets of three distinct disulfide-linked polypeptide chains (Aα, Bβ, and γ), whose synthetic programs are directed by three separate genes on chromosome 4. Thrombin's major molecular target is fibrinogen, which is converted to fibrin monomers as thrombin removes N-terminal fibrinopeptides A and B. The resulting monomer is a disulfide-linked trinodular protein whose N- and
Regulation of fibrinolysis
Like the coagulation cascade, fibrinolysis is tightly controlled by a series of cofactors, inhibitors, and receptors [5]. Plasmin is the primary fibrinolysin, and is activated from plasminogen by either of two primary serine proteases, tPA and uPA. Whereas tPA is synthesized and released by endothelial cells, uPA is produced by monocytes, macrophages, and urinary epithelium. Both activators have exceedingly short half-lives in circulation (4–8 minutes) due to the presence of high concentrations
Fibrin degradation products
Fibrin degradation products (FDPs) begin to form as plasminogen is activated and plasmin begins to degrade the thrombus. Multiple FDPs, including fibrinopeptide B and other fibrin degradation monomers and dimers are released [61], [62], [63]. When fibrin polymers are cleaved by plasmin at the D fragment site, the resulting D-dimer fragment reflects the degree of thrombosis and plasmin activity. D-dimer assays have found predictive and prognostic value in a number of disease states, including
Fibrinolysis and coagulation cofactor activity
In vitro evidence suggests that plasmin may inactivate factor Va by cleaving both its heavy and light chains. Similarly, it appears that plasmin can inactivate factor VIIIa, another procoagulant cofactor that is structurally related to factor Va [78], [79]. These cleavage events occur at sites distinct from those targeted by activated protein C [80].
Fibrinolysis and platelet function
Platelet glycoproteins IIb/IIIa and Ib, the cell surface receptors for fibrinogen and von Willebrand factor, respectively, are also plasmin
Lessons from hemophilia and inherited disorders of fibrinogen
There are numerous disease states that illustrate the importance of balanced fibrin formation and fibrin degradation. Although inherited bleeding disorders, such as hemophilia, reflect defects in the coagulation cascade upstream of fibrin formation, delayed bleeding develops as a result of abnormal fibrin structures yielding clots that are poorly adherent and easily dissolved. Impaired clot formation and structure can be restored by hemostatic treatments like recombinant factor VIIa [17], [18].
Acquired fibrinolytic disorders
Acquired disorders of fibrinolysis and fibrinolytic components have been described in many disease states. These disorders can be subdivided into hyper- and hypofibrinolytic groups as described below.
Congenital defects and variation in fibrinolysis
Numerous congenital defects in the fibrinolytic system have been described (Table 1A). Among congenital hypofibrinolytic disorders, livedoid vasculopathy is an occlusive vascular disorder affecting small blood vessels of the lower extremities that has been associated with elevated levels of PAI-1 due to a promoter polymorphism (4G/4G) that increases its production [115]. Ulcerations that occur in this disorder lead to development of white atrophic scars (atrophie blanche) as a result of a
Measuring global fibrinolysis in clinical practice
Fibrinolysis is difficult to measure directly, and assays remain poorly predictive of thrombosis or bleeding. In addition, developing a reliable test of fibrinolysis for clinical use has been difficult, and this may have precluded the identification of some fibrinolytic disorders. The complex interplay of hemostatic and fibrinolytic proteins makes it difficult to predict the development of thrombosis or bleeding. Moreover, interference from other variables such as inflammatory mediators and
Summary and future directions
The fibrinolytic system is as complicated and multifaceted as the coagulation cascade, and is equally relevant thrombotic disease and bleeding. Dysregulation of the fibrinolytic system is associated with diverse and unpredictable clinical phenotypes ranging from the coagulopathies of liver disease and DIC to rare congenital bleeding disorders. To date, global assays of fibrinolysis have shown promise in predicting risk of thrombosis but not bleeding, and more research in this area is needed. In
Practice points
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Disorders of fibrinolysis can be congenital or acquired in association with numerous medical conditions including malignancy, liver disease, and renal failure.
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Hypofibrinolysis is more often associated with thrombosis, while hyperfibrinolysis may result in a bleeding tendency.
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Defects in fibrinolytic components have been associated with non-hematologic manifestations such as ligneous mucositis.
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Global assays of fibrinolysis developed to predict thrombosis should be validated in larger populations,
Research agenda
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Improved understanding of hematologic and non-hematologic pathways of the fibrinolytic system in human disease.
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Validation of fibrinolysis testing to predict bleeding and thrombosis.
Disclosures
The authors report no relevant conflicts of interest.
Acknowledgements
Work related to this article was funded by grants from the National Institutes of Health (R01 HL042493 and R01 HL090895), the March of Dimes (FY12-356), and the Qatar Research Foundation (NPRP5-932-3-208 and NPRP6-736-3-187).
References (161)
- et al.
Platelets at work in primary hemostasis
Blood Rev
(2011) - et al.
Insights into platelet-based control of coagulation
Thromb Res
(2014) - et al.
Factor XIII, clot structure, thrombosis
Thromb Res
(2012) Thrombin generation and fibrin clot structure
Blood Rev
(2007)- et al.
Fibrinogen and red blood cells in venous thrombosis
Thromb Res
(2014) - et al.
Flow rate and fibrin fiber alignment
J Thromb Haemost
(2010) - et al.
Thrombin flux and wall shear rate regulate fibrin fiber deposition state during polymerization under flow
Biophys J
(2010) - et al.
Fibrin in human plasma: gel architectures governed by rate and nature of fibrinogen activation
Thromb Res
(1994) - et al.
Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk
Blood
(2003) Fibrin(ogen) and thrombotic disease
J Thromb Haemost
(2013)
Recombinant factor VIIa analog NN1731 (V158D/E296V/M298Q-FVIIa) enhances fibrin formation, structure and stability in lipidated hemophilic plasma
Thromb Res
Blood coagulation in hemophilia A and hemophilia C
Blood
The effect of fibrin structure on fibrinolysis
J Biol Chem
The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies
Blood
Dynamic changes of fibrin architecture during fibrin formation and intrinsic fibrinolysis of fibrin-rich clots
J Biol Chem
Fibrinogen gamma-chain splice variant gamma' alters fibrin formation and structure
Blood
Elevated plasma fibrinogen gamma' concentration is associated with myocardial infarction: effects of variation in fibrinogen genes and environmental factors
J Thromb Haemost
The fibrinogen γA/γ′ isoform does not promote acute arterial thrombosis in mice
J Thromb Haemost
New insights into the molecular mechanisms of the fibrinolytic system
J Thromb Haemost
Cellular receptors for the plasminogen activators
Blood
Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin
J Biol Chem
A study of the protection of plasmin from antiplasmin inhibition within an intact fibrin clot during the course of clot lysis
J Biol Chem
Plasminogen activator inhibitors
Blood
Concentrations of plasminogen activators and their inhibitors in blood preconceptionally, during and after pregnancy
Eur J Obstet Gynecol Reprod Biol
Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma
Blood
The presence and release of alpha 2-antiplasmin from human platelets
Blood
Factor XIII-mediated cross-linking of NH2-terminal peptide of alpha 2-plasmin inhibitor to fibrin
FEBS Lett
Cross-linking site in fibrinogen for alpha 2-plasmin inhibitor
J Biol Chem
The novel plasminogen receptor, plasminogen receptor(KT) (Plg-R(KT)), regulates catecholamine release
J Biol Chem
Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane
J Biol Chem
Identification and characterization of human endothelial cell membrane binding sites for tissue plasminogen activator and urokinase
J Biol Chem
The annexin A2 system and vascular homeostasis
Vascul Pharmacol
Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome
Blood
Genetic predictors for stroke in children with sickle cell anemia
Blood
The coagulopathy of acute promyelocytic leukaemia revisited
Best Pract Res Clin Haematol
Regulation of S100A10 by the PML-RAR-α oncoprotein
Blood
The clotting of fibrinogen. I. The liberation of peptide material
Biochim Biophys Acta
Selective D-dimer testing for the diagnosis of acute deep vein thrombosis: a validation study
J Thromb Haemost
Variable D-dimer thresholds for diagnosis of clinically suspected acute pulmonary embolism
J Thromb Haemost
Identification of a region of the fibrin molecule involved in upregulation of interleukin-8 expression from human oral squamous cell carcinoma cells
Arch Oral Biol
Inactivation of factor Va by plasmin
J Biol Chem
Proteolysis of platelet glycoprotein by plasmin is facilitated by plasmin lysine-binding regions
Blood
The roles of protein C and thrombomodulin in the regulation of blood coagulation
J Biol Chem
Purification and characterization of TAFI, a thrombin activatable fibrinolysis inhibitor
J Biol Chem
gamma-Chain dysfibrinogenemias: molecular structure-function relationships of naturally occurring mutations in the gamma chain of human fibrinogen
Blood
Thrombin induces angiogenesis and vascular endothelial growth factor expression in human endothelial cells: possible relevance to HIF-1alpha
J Thromb Haemost
Pharmacokinetics and safety of fibrinogen concentrate
J Thromb Haemost
Fibrinogen replacement therapy for congenital fibrinogen deficiency
J Thromb Haemost
Pathogenesis of thrombosis
Hematology Am Soc Hematol Educ Program
The molecular basis of fibrinolysis
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