What Controls The Size Of A Clot

Introduction

Fibrinogen, a plasma 340-kDa glycoprotein, is converted to fibrin on express proteolysis by thrombin.^1,2 The protein is very heterogeneous because of variations in partial proteolysis, phosphorylation or sulfation of amino acids, genetic polymorphisms, and alternative splicing.³ Fibrinogen consists of 2Aα-, 2Bβ-, and 2γ-chains, linked in a dimeric construction by 29 disulfide bonds. The Bβ and γ C-termini compose the D-region, whereas the E-region contains the N- termini of all six chains. The D-regions are continued to the E-region by two α-helical coiled coil segments (Effigy ane). The Aα C-termini are globular and located shut to the E-region in fibrinogen.^4–6

**Figure 1.** Fibrinogen and fibrin formation. Fibrinogen is composed of 2Aα, 2Bβ, and 2γ-chains, which are arranged in a dimer of bilateral symmetry. The central Eastward-region contains the N-termini of all 6 bondage. The D-region, which is connected with the E-region by a coiled coil segment, is composed of the β- and γ-concatenation C-termini. The α-chain C-termini fold back on the coiled scroll and interact with the E-region. Fibrin germination involves cleavage of FpA (orange) by thrombin (fibrin I), which polymerizes into protofibrils. Subsequently, FpB (green) is cleaved by thrombin (fibrin Two). FpB cleavage is associated with release of the C-terminal α-domains, which interact for lateral aggregation.

Fibrin formation is initiated by thrombin-mediated release of fibrinopeptide (Fp)A and FpB from the Aα and Bβ North-termini, respectively. In solution, cleavage of FpA occurs kickoff, inducing polymerization into protofibrils of one-half-staggered, overlapping fibrin units (Figure 1).^i,2 FpB is cleaved at a slower rate than FpA by thrombin. Fibrinopeptide release undergoes dissimilar kinetics when fibrinogen is leap to a surface. Riedel et al recently showed that FpB release is increased, specially from fibrinogen with "terminate-on" as opposed to "side-on" surface zipper.⁷ Surface-related fibrin deposition may play a role in stent or cardiopulmonary featherbed thrombosis, on cells and subendothelial structures. FpB release is associated with lateral aggregation of protofibrils, which is caused by interacting αC-terminal domains (Figure ane).^6,8,ix Lateral aggregation contributes to fiber thickness and tensile forcefulness of fibrin.^ix,x The overall mechanical properties of fibrin are determined past structural features at the level of the molecule, individual fibers, and the branched fiber network.^eleven–13

Fibrin cantankerous-linking by activated gene (F)XIII improves the elastic properties and resistance to fibrinolysis.^xiv–17 γ-Chain cross-links occur betwixt lysine 406 on 1 concatenation and either glutamine 398 or 399 on another.^{16,xviii,nineteen} α-Chain cross-linking results in oligomer and polymer formation. FXIIIa also cross-links α₂-antiplasmin, thrombin-activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor-2 to fibrin, contributing to its resistance to fibrinolysis.^twenty–23 The importance of cantankerous-linking by FXIIIa is highlighted past the severe bleeding associated with its deficiency.²⁴

Fibrinolysis is mediated by interaction of tissue plasminogen activator (tPA) and plasminogen.^25,26 Fibrin greatly accelerates the conversion of plasminogen to plasmin past tPA.²⁶ Plasmin cleaves Lys-10 and Arg-X bonds in fibrin, breaking downwards the fiber structure.

Plasminogen and tPA bind to lysine residues exposed past fibrinolysis, further accelerating the conversion of plasminogen into plasmin. Plasmin that is bound to fibrin is relatively protected from inhibition by circulating α₂-antiplasmin.²⁷ However, α₂-antiplasmin also binds to fibrin and helps to protect the clot against fibrinolysis.^20,21

A key inhibitor of tPA, plasminogen activator inhibitor-1 (PAI-1), is released from platelets and the endothelium on stimulation with cytokines or thrombin. Urokinase-blazon plasminogen activator primarily participates in jail cell-mediated plasmin generation.²⁸ Urokinase-type plasminogen activator is expressed by kidney and tumor cells and participates in angiogenesis past binding to its endothelial receptor urokinase-type plasminogen activator receptor. Urokinase-blazon plasminogen activator lyses the clot, allowing tubular in-growth of new endothelium. TAFI downregulates plasmin generation by removing C-terminal lysine residues on fibrin, resulting in increased stability of thrombi.²⁹

Fibrin construction itself straight affects fibrinolysis rates,³⁰ and mechanisms that control this have recently been reviewed.³¹ Longstaff et al³² recently showed that accessibility of the clot to fibrinolytic proteins and alterations in binding of tPA and plasminogen were both regulated by fibrin structure. Fibrinolysis proceeds rapidly in platelet-poor areas of the clot, whereas platelet-rich areas remain relatively unlysed.³³ Fibrin networks composed of the thin, highly branched fibers are less permeable, more rigid, and less susceptible to lysis. Clots composed of thick fibers take larger pores, leading to higher permeability and accelerated fibrinolysis.^30–33 Fibrinogen concentrations explain up to 18% of the variation in jell permeability.³⁴

Modulators of Fibrin Properties

A number of genetic and environmental factors correlate with fibrin structure and its clan with thrombotic disease. These are discussed below and summarized in Effigy 2.

**Figure 2.** Fibrin clot structure and thrombembolic diseases. Shown are affliction states reportedly associated with abnormal alterations of fibrin jell structure and part, particularly reduced clot permeability and susceptibility to lysis, and postulated modifiers of fibrin clot characteristics. A, Atherothrombosis. B, Venous thromboembolism. C, Inflammatory disorders. CRP indicates C-reactive poly peptide; Hcy, homocysteine.

Genetic Factors

Genetic factors contribute moderately to variance in fibrin structure.^34,35 Quantitative trait loci for fibrin structure are located in chromosomes 5, 6, ix, 16, and 17.³⁶ Odds ratios of more 1000:1, expressed logarithmically as a logarithm of odds score of >three, are considered meaning genetic linkage in humans. Six regions with logarithm of odds score >3 have been identified.³⁶ For nigh fibrin characteristics, heritability ranges from x% to 40%.^34,37

Each fibrinogen chain is encoded by a separate gene, all three of which are located in the same region on chromosome iv (4q28.1, 4q28.2, and 4q28.3 for FGG, FGA, and FGB, respectively).³⁸ Fibrinogen synthesis involves assembly of the hexamer in the endoplasmic reticulum, with β-concatenation incorporation as rate-limiting step.³⁹ Dysfibrinogenemias resulting from mutations in the fibrinogen genes are linked with arterial or venous thrombosis in ≈25% of cases. An excellent review on inherited fibrinogen abnormalities has been published recently.⁴⁰

Fibrin structure may also be influenced past common genetic variation. A mutual β-chain polymorphism, Lys448Arg, has been shown to touch on jell structure in plasma,⁴¹ Recombinant Lys448 and Arg448 fibrinogens also showed differences in fibrin structure, both in purified systems and in plasma. The recombinant variants significantly afflicted lysis times when reconstituted in plasma.⁴² There is further evidence linking jell structure with an α-chain Thr312Ala polymorphism. The Ala312 allele has been associated with thicker fibrin fibers, increased α-concatenation cross-linking by FXIIIa,⁴³ and higher mortality in patients with atrial fibrillation complicated by ischemic stroke, by predisposing to arterial embolization.⁴⁴

A fibrinogen γ-chain splice variant, γ′, leads to the substitution of 4 C-final residues containing a platelet binding site with xx new residues that contain both thrombin and FXIII B-subunit binding sites.⁴⁵ Clots produced with γ′ fibrinogen have thinner fibers, more than branch points, and increased resistance to lysis.⁴⁶ Based on scanning electron microscopic identification of capped fiber ends, accuse-charge repulsion by the negatively charged γ′ concatenation were suggested to play a role in dumb polymerization,⁴⁷ a hypothesis that deserves further investigation. Taken together, these studies show that mutual genetic variations in all fibrinogen polypeptide chains tin can influence fibrin structure and function, which ultimately may translate into altered risk for thrombosis.

FXIII polymorphisms accept also been associated with alterations in fibrin construction. A Thousand>T transition in codon 34, with subsequent replacement of valine with leucine (FXIII Val34Leu), significantly alters fibrin structure. Thrombin demonstrates higher catalytic efficiency when activating FXIII Leu34 compared with Val34.^48–l Early activation of FXIII results in the germination of clots with smaller pores and thinner fibers.⁴⁸ In that location is evidence that the Leu34 allele protects against myocardial infarction (MI) and venous thrombosis.^51,52 Increased FXIII activation in Leu34 carriers may outcome in ineffective cantankerous-linking.⁴⁹ The apparent discrepancy betwixt increased FXIII activation and protection against MI may as well be due to interactions between Val34Leu and fibrinogen concentrations.⁴¹ At high fibrinogen concentrations, FXIII Leu34 leads to the formation of more permeable clots that are more susceptible to lysis, whereas at a low fibrinogen concentration, the furnishings were reversed, suggesting that protection confronting thrombosis by FXIII 34Leu occurs merely at elevated fibrinogen levels.

Thrombin

(Pro)thrombin concentration has a major affect on fibrin construction. Wolberg et al showed that fibrin fiber bore decreases with increasing prothrombin levels.⁵³ In both purified fibrinogen and plasma-based systems, clots produced with high thrombin concentrations are characterized past thin fibers that form a network with minor pores.⁵⁴ There potentially are many factors that influence both thrombin generation and fibrin clot structure. Examples of the latter include anticoagulant drugs that have been shown to influence fibrin construction through reduced thrombin generation. Of note, some other modifiers of fibrin structure/office, such as statins, might also at to the lowest degree in part alter fibrin characteristics through reduced thrombin action (see below).

Reduced thrombin generation in hemophilia B has been associated with the formation of loosely packed fibrin susceptible to lysis.⁵⁵ In addition, reduced TAFI activation in hemophilia leads to increased susceptibility to fibrinolysis.⁵⁶ Recombinant activated FVII increases thrombin generation rates, normalizing fibrin structure and increasing jell stability.⁵⁵

The Factor V Leiden and G20210A prothrombin mutations are the most common genetic thrombophilic factors in whites that increase thrombin generation.⁵⁷ To our noesis, there are no studies on fibrin structure in carriers of these mutations. I interesting report showed that whereas carrier status of Factor V Leiden increases venous thromboembolism (VTE) risk 3.5-fold, when combined with hypofibrinolysis, the risk is increased eight.1-fold.⁵⁸ In contrast, prolonged lysis time together with prothrombin 20210A did not synergistically heighten risk.⁵⁸ Individuals with the prothrombin G20210A allele showed normal fibrin elastic moduli.⁵⁹

Thrombin generation is a dynamic, localized process, and the germination of fibrin is adamant by cellular procoagulant activity, which leads to spatial heterogeneity in jell structure associated with the distance of fibrin from the jail cell surface.⁶⁰ A denser fibrin network is formed within x μm of the prison cell, as shown in experiments on human fibroblasts incubated with the prothrombinase complex and fibrinogen or plasma.^sixty Stimulation of endothelial cells with cytokines causes the germination of compact fibrin networks resistant to lysis.⁶¹ The molecular mechanisms that regulate clot structure close to the endothelium are unknown but could involve local tissue factor activeness, changes in thrombomodulin concentration, or the endothelial fibrin(ogen) receptor α_Vβ₃.

Blood Period

Fibrin fibers are aligned in the direction of flow, which has important implications for clot elastic backdrop and response to fibrinolysis.^62–64 Fibrin fibers are more than resistant to stretch than flexion, and hence fiber alignment in the direction of catamenia will increment clot stiffness in that direction. One written report found no effect of flow on fiber diameter,⁶² whereas another reported formation of thicker fibers in the direction of menses, with thinner fibers interconnecting these larger fibers perpendicularly.⁶³ Changes in fiber bore influence plasmin generation and the resistance to fibrinolysis.

Oxidative Stress

Fibrinogen is particularly susceptible to oxidation, ≈20× more than than albumin.⁶⁵ Fibrinogen may therefore scavenge oxidants and protect other proteins from oxidation. Fibrinogen oxidation post-obit exposure to oxygen, metal, and myeloperoxidase-derived oxidants decreases the rate of clot germination.⁶⁵ Yet, other investigators reported that exposure of fibrinogen to Fe³⁺ ascorbate promotes fibrin formation, enhances platelet assemblage, and supports less efficient plasminogen activation by tPA.^66,67 Studies on air pollution accept shown that ultrafine particulate matter can modulate fibrin structure in an oxidation-dependent manner. Addition of antioxidants reversed this issue.⁶⁸

Nitration of 2 β-concatenation tyrosines increases fibrin formation and stiffness, impairs clot lysis, and alters fibrin structure.⁶⁹ Data on the association betwixt oxidative stress markers and fibrin clot properties in vivo are deficient. F_ii-isoprostanes, produced on nonenzymatic arachidonic acid peroxidation and a stable mark of oxidative stress, have been shown to associate with reduced jell permeability and fibrinolysis in cardiovascular patients.^lxx Taken together, these studies suggest that oxidative stress may promote prothrombotic alterations in fibrin formation and architecture.

However, clinical trials failed to prove benefits from antioxidant therapies in diseases believed to be associated with oxidative stress such as atherosclerotic vascular disease.⁷¹ It has been postulated that the antioxidant therapy did not last long enough to reveal the beneficial effects in cardiovascular patients. Moreover, in vitro evidence suggests that fibrinogen oxidation may both impair and enhance the ability to form stable fibrin clots; thus, in the presence of additional modifiers of fibrin, the net effect could exist different in subjects at various cardiovascular risk. Additional studies are needed to elucidate the in vivo effects of oxidative stress on fibrin structure and function.

Platelet Activation

Proteins released from platelets alter clot properties, particularly at sites of platelet aggregation. Increased amounts of platelet factor 4 are associated with the germination of a compact jell structure.⁷² Polyphosphate, a negatively charged polymer of inorganic phosphate secreted from dense granules, also modifies the fibrin network and its plasmin-mediated degradation.^73–75 The effects of polyphosphate on jell structure are calcium dependent and independent from FXIII activation.⁷³ Polyphosphates atomic number 82 to the formation of tight cobweb aggregates interspaced with large pores.⁷⁴ Fibrinolysis is impaired considering of reduced binding of plasminogen and tPA to partially lysed fibrin.⁷⁴ Pyrophosphate, besides released from activated platelets, blocks polyphosphate-induced enhancement of fibrin polymerization.⁷⁵ The effect of polyphosphate depends on polymer length and the highest fibrin turbidity is induced by polyphosphate of >250-mers,⁷⁵ although 65-mers, the size of polyphosphate released past platelets, as well evidence significant furnishings.⁷⁴ Platelets as well release PAI-1 that contributes to impaired fibrin degradation and the role of PAI-1 in clot lysis increases with the number of platelets.⁷⁶

Lipoprotein(a)

Lipoprotein(a) contains apolipoprotein(a), whose Kringle domains are homologous with plasminogen Kringles Four and Five. Elevated lipoprotein(a) levels correlate with decreased fibrin permeability, thinner fibers, and reduced susceptibility to fibrinolysis.⁷⁷ The relationship between lipoprotein(a) and clot properties depends on apolipoprotein(a) isoforms, whereby small-scale isoforms are responsible for abnormal fibrin characteristics.⁷⁷ Molecular mechanisms underlying apolipoprotein(a)-related changes in jell properties remain unclear. The fibrin(ogen) αC-regions contain apolipoprotein(a)-binding sites.⁷⁸ Additional studies are required to investigate how these binding sites may play a office in fibrin construction and fibrinolysis.

Modulation Related to Mechanisms of Disease

Diabetes Mellitus

Abnormal fibrin jell properties accept consistently been associated with diabetes. Increased fibrinogen levels observed in type 2 and blazon one diabetes correlate with the degree of hyperglycemia. Clots formed from patients with diabetes using purified fibrinogen or plasma are less porous than controls.⁷⁹

Altered fibrin structure in diabetes is attributed to fibrinogen glycation, which interferes with fibrin polymerization, cross-linking by FXIII, tPA and plasminogen binding, and plasminogen to plasmin conversion.⁸⁰ Fibrinogen glycation occurs in vivo and correlates with hyperglycemia.^79–82 Fibrinogen purified from patients with diabetes produces clots that are denser and resistant to fibrinolysis.^80,81 These studies point to pathophysiological mechanisms whereby fibrinogen glycation produces abnormal clot structures that contribute to thrombosis risk (Figure 3). Treatment with insulin makes fibrin more permeable through changes in fibrinogen levels.⁸³

Figure 3. — **Effigy three.** Mechanisms of fibrinogen glycation, fibrin structure, and risk of thrombosis. Diabetes and insulin resistance are associated with hyperglycemia. Hyperglycemia over a prolonged period of time will lead to nonenzymatic glycation of plasma proteins, including fibrinogen. Glycated fibrinogen leads to denser fibrin clots that are stiffer and more resistant to fibrinolysis, thus leading to an increased thrombotic burden.

Hyperhomocysteinemia

Homocysteine (Hcy), produced through methionine metabolism, is associated with an increased hazard for coronary avenue disease (CAD) and thrombosis. In rabbits, hyperhomocysteinemia is associated with the formation of fibrin with thinner and more tightly packed fibers and increased resistance to fibrinolysis.⁸⁴ Hcy addition in vitro results in the germination of plasma clots with shorter fibers and a more compact structure.⁸⁵ The ε-amino group of fibrinogen lysines can be modified by a highly reactive thioester, Hcy thiolactone, nowadays in small amounts in plasma.⁸⁶ Ten lysines in the D- and αC-regions can be homocysteinylated.⁸⁷ Homocysteinylation introduces free sulfhydryl groups and increases the size of the modified amino acrid. The increased resistance to fibrinolysis on homocysteinylation is in part due to a decreased ability of modified fibrin to support tPA-induced plasminogen activation.⁸⁷

Elevated total Hcy (tHcy) is associated with reduced clot porosity and enhanced lysis resistance in both apparently healthy men and in patients with avant-garde CAD.⁸⁸ Astute hyperhomocysteinemia following methionine load did not affect these properties, whereas folate-induced reduction in Hcy resulted in increased clot permeability and improved clot lysability.⁸⁸ Hcy lowering trials, however, failed to reduce cardiovascular events, thus casting dubiousness on the causative role of Hcy in atherosclerotic vascular disease. A recent assay suggests that cardiovascular hazard prediction by tHcy is confined to the Hcy fraction that does not respond to B-vitamins.⁸⁹ There are mechanisms that are "resistant" to Hcy-lowering action of folic acid. For example, elevated tHcy tin can effect in production of autoantibodies directed confronting N-Hcy-poly peptide adducts,⁸⁶ that tend to remain increased despite reduction in tHcy.⁹⁰ Moreover, beneficial effects of Hcy-lowering could exist adulterate by other prothrombotic modulators of fibrin characteristics such as diabetes.⁸⁸ Additional studies are needed to investigate the effect of reduced tHcy on fibrin clots in a wide spectrum of cardiovascular patients.

Smoking-Related Diseases

Cigarette smoking increases thrombotic adventure via multiple mechanisms, including a marked increase in fibrinogen levels. It has been reported that following acute exposure to cigarette fume, fibrin clots are denser and composed of thinner fibers compared with nonsmoking and presmoking samples.⁹¹ Thromboelastography performed in whole blood before and later on smoking 2 cigarettes showed lower lysis efficiency.⁹²

In apparently healthy men who reported cigarette smoking for five years or more, current smoking is associated with 22% lower clot permeability and 35% longer jell lysis compared with never smokers.⁹³ These smoking-related fibrin abnormalities appear to exist determined largely by elevated fibrinogen and enhanced oxidative stress.⁹³

Drug-Related Modulation

Acetylsalicylic Acid (Aspirin)

Aspirin increases clot permeability and fiber mass-length ratio past up to 65% (Tabular array 1).⁹⁴ Of note, a dose of 320 mg/day exerts a weaker effect on fibrin properties than a lower dose of 75 mg/mean solar day.^94,95 The machinery backside this nonlinearity is unknown. Seven days after aspirin withdrawal, clot permeability returns to baseline.⁹⁶ Aspirin-related increases in jell pore size in stable CAD have also been associated with enhanced clot lysability.⁹⁷

**Table 1.** Interventions and Factors That Have Been Suggested as Potential Modifiers Favorably Altering Fibrin Clot Properties
Modulatory Mechanisms	Interventions
Subtract in thrombin generation	Treatment with anticoagulants,^110–112 statin utilize^104–107
Reduction in oxidative stress	Cessation of smoking^91–93
Improved glycemic control	Treatment with insulin⁸³ and metformin¹⁰⁸
Decrease in total homocysteine	Administration of folic acrid⁸⁸
Decrease in C-reactive protein	Statin use^104,105
Acetylation of proteins	Aspirin^94–99
Other or unknown	Fibrates, angiotensin-converting enzyme inhibitors¹⁰⁴

In an in vitro cellular model of fibrinogen acetylation by aspirin, fibrin clots were produced that were less meaty, with thicker fibers.⁹⁸ Acetylation reduced jell rigidity by 30% and enhanced jell lysis, which was confirmed with fibrinogen purified from good for you individuals receiving 150 mg/day aspirin for 7 days.⁹⁸ Bjornsson et al demonstrated that in vitro acetylation of purified fibrinogen impairs the ability of fibrin to polymerize and decreases clot stability.⁹⁹ An inverse correlation exists betwixt the extent of fibrinogen acetylation and clot lysis.⁹⁹ In vitro aspirin inhibits fibrinogen oxidation, which further enhances fibrinolytic efficiency.⁶⁶

Aspirin inhibits FXIII activation because of adulterate of thrombin generation.¹⁰⁰ Aspirin-related impairment of FXIII activation, evaluated at the site of microvascular injury, is more pronounced in Leu34 carriers than in subjects homozygous for the Val34 allele.¹⁰⁰ These observations advise the being of fibrin-associated facets of aspirin resistance,¹⁰¹ which may exist of importance during the prevention or treatment of thrombosis with low-dose aspirin.

Statins

There is compelling evidence that statins reduce cardiovascular morbidity and bloodshed.¹⁰² The JUPITER (Justification for the Apply of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study demonstrated that rosuvastatin reduces venous thrombosis chance in normocholesterolemic individuals during a 1.9-year follow-up.¹⁰³

Apart from cholesterol-lowering furnishings, statins attenuate coagulation and lead to alterations in fibrin characteristics. A iv-calendar week handling with simvastatin or atorvastatin associated with increased fibrin permeability and shorter lysis time.¹⁰⁴ Of note, clot properties correlated with decreased thrombin generation, most likely induced by downregulation of tissue factor. In subjects with depression-density lipoprotein cholesterol below iii.4 mmol/Fifty, simvastatin was also shown to increase clot permeability associated with faster lysis. This correlated with a reduction in C-reactive protein (CRP) (see below).¹⁰⁵ Increased fibrin permeability following statin assistants tin exist observed even in diabetic patients with dyslipidemia.¹⁰⁶ Interestingly, fibrates such as gemfibrozil have no effects on fibrin permeability¹⁰⁷ except for micronized fenofibrate, which exerts additional antithrombotic and antiinflammatory actions.¹⁰⁴ Information technology is unclear whether fibrin-modulating effects contribute to cardiovascular benefits of statins, and additional studies are required to address this.

Angiotensin-Converting Enzyme Inhibitors

Data on the consequence of angiotensin-converting enzyme inhibitors on fibrin are sparse. Quinapril at 10 mg/day for ane month increased clot permeability independently of antihypertensive outcome.¹⁰⁴ Depressed thrombin germination afterwards handling with angiotensin-converting enzyme inhibitors in CAD patients associated with improved jell permeability. It might exist speculated that antithrombotic effects could contribute to clinical efficacy of angiotensin-converting enzyme inhibitors; however, future studies volition be required to investigate this further.

Glucose-Lowering Agents

Glucose lowering agents might indirectly affect clot structure by decreasing fibrinogen levels or extent of fibrinogen glycation, however data concerning this are inconsistent. Metformin affects the fibrin structure by dissimilar mechanisms. Metformin interferes with fibrin polymerization and reduces FXIII-mediated cross-linking leading to increased lysability.¹⁰⁸ Increased jell permeability has also been demonstrated in obese, nondiabetic individuals taking metformin.¹⁰⁹

Anticoagulants

Anticoagulant treatment with vitamin K antagonists, heparins, direct thrombin inhibitors (argatroban, bivalirudin, lepirudin, dabigatran), and indirect (danaparoid, fondaparinux) and direct activated cistron X inhibitors (rivaroxaban, apixaban) affects fibrin characteristics and lysis through reduced thrombin generation. Warfarin (international normalized ratio two to iii) increased fibrin permeability by 28% to 50%.¹¹⁰ Similar increases in clot permeability are observed at therapeutic plasma concentrations of fondaparinux and apixaban (by 58% to 76% and 36% to 53%, respectively).¹¹⁰

Looser clot structure has also been shown in the presence of other anticoagulants.¹¹¹ Direct thrombin inhibitors increment clot susceptibility to lysis and this upshot is in part mediated by TAFI.¹¹² Reduced thrombin generation during anticoagulation account for the formation of less compact and more lysable fibrin, without major differences in the effects observed with old or new anticoagulants. Nonetheless, whereas activated coagulation factor concentrates completely reverse changes in fibrin properties following warfarin, the effects of newer anticoagulants are only partly reversed.¹¹⁰

Jell Properties in Disease

Fibrin structure has been associated with a number of thromboembolic diseases, which we review in the following section. Tabular array 2 summarizes associations between thromboembolic diseases and altered fibrin properties.

**Table ii.** Studies on Associations Betwixt Vascular Disorders and Fibrin Backdrop
Disease	No. of Subjects	Written report Design	Measurements	Clot Phenotype	Ref.
Acute MI	40	Case-control	Permeation, turbidity, lysis assays, microscopy	↓K_s ↑lysis time ↑fiber thickness ↓lag phase	70
Previous MI	38	Case-command	Permeation	↓K_s	114
	33	Case-control	Rigidity, lysis assays, microscopy	↓rigidity	117
				↑lysis time
				↓cobweb thickness
	198	Case-control	Lysis assay	↑lysis fourth dimension	129
	555	Case-command	Lysis analysis	↑lysis fourth dimension	118
Astute stroke	45	Case-control	Permeation, turbidity, lysis assays, compaction, microscopy	↓K_southward ↓compaction	127
				↑lysis time ↑fiber thickness
				↓lag phase
	xx	Case-control	Permeation, lysis assays	↓K_s	126
				↑lysis time
Previous stroke	147	Case-control	Permeation, turbidity, lysis assays, microscopy	↓K_south ↑lysis time ↑fiber thickness	124
				↓lag phase
				↑lysis fourth dimension
	103	Instance-control	Lysis assay		129
In-stent thrombosis	47	Instance-control	Permeation, turbidity, lysis assays, compaction	↓K_s ↓compaction	121
				↑lysis time
Advanced CAD	133	Case-control	Permeation, lysis analysis, microscopy	↓lag stage
				↓One thousand_s	115
				↑lysis time
				↑cobweb thickness
	eighteen	Instance-control	Permeation	↓1000_s	113
Peripheral arterial illness	106	Cohort	Permeation, turbidity, lysis assays	↓1000_{due south} ↑lysis fourth dimension	127
				↓lag phase
	34	Example-control	Permeation, turbidity, lysis assays, microscopy	↓Thou_s ↓fiber thickness	128
				↑lysis time
	34	Case-control	Lysis analysis	↑lysis time	129
Venous thrombo- embolism*	100	Example-control	Permeation, turbidity, lysis assays, compaction	↓K_southward ↓compaction	135
				↑lysis time ↑cobweb thickness
	421	Example-control	Lysis assay	↑lysis time	132
	2090	Case-command	Lysis assay	↑lysis time	58
Diabetes mellitus	twenty (type 1)	Case-control	Permeation	↓Grand_s	79
	150 (type 2)	Example-control	Permeation, lysis assays, microscopy	↓G_s	80, 81
				↑lysis time
				↓fiber thickness
Terminate-stage renal disease	22	Case-control	Permeation, turbidity, compaction, lysis assay, microscopy	↓Grand_s ↓compaction ↑lysis time	136
				↑fiber thickness
				↓K_s ↓compaction
	33	Instance-control	Permeation, turbidity, compaction, lysis assays	↓lag stage ↑lysis time ↑fiber thickness	137
COPD	56	Instance-command	Permeation, compaction, lysis assays, microscopy	↓M_{due south} ↓compaction	138
				↑lysis time
				↓lag phase
Rheumatoid arthritis	46	Case-control	Permeation, turbidity, lysis assays, microscopy	↓K_south ↑lysis time projections on fibers ↓lag phase	140

CAD

Altered clot structure was outset demonstrated in patients with advanced CAD in 1992.¹¹³ Fibrin composed of dumbo fiber networks, which display ≈thirty% reduced permeability, was found in men with MI, aged less than 45 years.^113,114 It has been estimated that ≈50% of CAD patients accept clot permeability beneath the 10th percentile of control.¹¹⁴ Increased clot permeability and lysis times were also observed in patients with advanced CAD aged lx years or older.¹¹⁵ Fibrin is a consistent component of atherosclerotic plaques, and its presence may promote plaque growth.¹¹⁶

Collet et al reported that clots from 33 young survivors of MI had increased stiffness and shorter fibers and were associated with slower fibrinolysis.¹¹⁷ Patients anile below 50 years after a first MI had longer clot lysis, which was associated with body mass index, blood pressure, and CRP.¹¹⁸ Outset-degree relatives of patients with MI have similar only milder alterations in fibrin structure.¹¹⁹

Compared with stable CAD, acute coronary events are associated with less permeable and lysable clots in plasma drawn within the start 12 hours from the onset of breast pain.⁷¹ Moreover, clots from patients with acute MI independent thicker fibers and began polymerization faster than those of stable angina patients matched for potential confounders. In contrast to stable angina, clot permeability and fibrinolysis in acute coronary event patients were determined past the degree of oxidative stress and inflammation.⁷⁰ Acute hyperglycemia, observed in up to 50% of acute MI patients, worsened efficiency of fibrinolysis just had no event on clot permeability.¹²⁰

Fibrin clot properties take been implicated in 2 life-threatening complications associated with invasive treatment of CAD, namely stent thrombosis and no-reflow phenomenon.^121,122 Based on autopsy studies showing a lack of complete endothelialization and persistent fibrin thrombi as a primary substrate underlying stent thrombosis, we investigated jell permeability and susceptibility to lysis in patients who survived such thrombotic event. Patients with stent thrombosis showed a more tightly packed and less porous fibrin construction.¹²¹ These alterations could prolong the presence of fibrin in the lumen. Interestingly, these findings point that autonomously from other factors associated with stent thrombosis (including the procedure itself, patient and lesion characteristics, stent blueprint, and premature cessation of antiplatelet drugs), fibrin-related factors might contribute not only to late thrombosis but too acute and subacute stent thrombosis, in particular when stent malapposition or underexpansion are excluded. Similarly, aberrant fibrin structure has been observed in patients with a history of the no-reflow phenomenon, defined as the absence of a complete myocardial perfusion despite successful opening of the infarct-related avenue.¹²²

Ischemic Stroke

Plasma obtained post-obit cerebrovascular ischemic events formed 20% denser clots compared with controls.¹²³ Fibrin backdrop showed an association with stroke severity but not with poststroke bloodshed during a seven-year follow-up.¹²³ Ischemic stroke of unknown origin, representing ane quarter of all cases, might be peculiarly associated with abnormal fibrin features. Patients with cryptogenic stroke showed dense clots resistant to lysis.¹²⁴ Ischemic stroke in the acute phase is associated with abnormal fibrin properties,¹²⁵ which are similar to those encountered in acute MI subjects,^lxx indicating that reduced clot permeability and lysis represent common features in patients with cardiovascular affliction complicated past ischemic events.

Patients with acute stroke and concomitant CAD showed prolonged clot lysis compared with those without a history of CAD. Fibrin jell compaction correlated with neurological deficit both on access and at discharge of patients admitted for acute ischemic stroke.¹²⁵ Lower clot permeability and reduced fibrinolysis observed in the acute phase of ischemic stroke do non change later on sixty days from the issue, suggesting that hypofibrinolysis is a persistent characteristic of ischemic stroke.¹²⁶ Overall, ischemic stroke is linked with fibrin structure alterations that underlie mutual mechanisms leading to cerebrovascular and coronary thromboembolic episodes. Given the fact that ischemic stroke is a highly heterogeneous pathology, it is unclear whether all types of ischemic strokes share like fibrin characteristics.

Peripheral Arterial Illness

Peripheral arterial disease (PAD) has a prevalence between iii% and 10% in the full general population and is associated with a 6-fold increase in cardiovascular bloodshed. Plasma obtained from patients with PAD formed fibrin clots with reduced permeability and susceptibility to lysis.¹²⁷ During follow-upward, clot phenotype was associated with an increased chance for thromboembolic events and the progression of PAD.¹²⁷ Bhasin et al reported on 34 relatively young patients with mild to moderate PAD in whom plasma fibrin clots were poorly permeable, rigid, and resistant to lysis, with increased cobweb thickness.¹²⁸

Hypofibrinolysis was associated with a 2.3-fold college odds ratio of PAD.¹²⁹ Commencement-caste relatives of PAD patients showed like jell characteristics,¹³⁰ providing evidence for genetic regulation of fibrin characteristics in PAD. PAD therefore appears associated with unfavorable clot characteristics, reflected to some extent by the overall atherosclerotic burden.

VTE

Thrombophilia screening fails to identify predisposing factors in thirty% to 50% of patients with idiopathic VTE, including deep-vein thrombosis and pulmonary embolism. Curnow et al showed that hypercoagulable patients with arterial thrombosis or VTE, pregnancy complications, or autoimmune diseases have increased fibrin generation and reduced fibrinolysis.¹³¹ Several studies documented reduced efficiency of clot lysis in VTE patients. Hypofibrinolysis has been shown in subjects following the first deep-vein thrombosis episode.¹³² A 2-fold increased deep-vein thrombosis adventure has been found in subjects with clot lysis times above the 90th percentile.¹³² Upwardly to 77% of clot lysis time variation in venous thrombosis patients can exist attributed to PAI-one, TAFI, prothrombin, and α₂-antiplasmin levels, with minimal contribution of fibrinogen levels.¹³³ Three established risk factors for VTE, namely oral contraceptives, immobilization, and FV Leiden, markedly increment the adventure associated with longest clot lysis time.⁵⁸ Recently, a 3.4 fold higher hazard of Budd-Chiari syndrome has been reported in subjects with least efficient fibrinolysis, and this was in office associated with elevated PAI-1 action, simply non TAFI.¹³⁴

Afterwards excluding known thrombophilia, cancer, trauma, surgery, pregnancy, and other established take a chance factors, VTE patients and their first-order asymptomatic relatives are characterized by lower clot permeability, lower compaction, higher maximum clot absorbancy, and prolonged clot lysis time than controls, with more pronounced abnormalities in patients versus relatives.¹³⁵ Interestingly, fibrin clots obtained for pulmonary embolism patients were more permeable, were less meaty, and lysed more efficiently compared with those of deep-vein thrombosis patients.¹³⁵ These findings support the concept of similar pathophysiology involving alterations of fibrin structure in both arterial and venous thrombosis. It is unclear whether VTE patients with transient take a chance factors such every bit surgery or trauma display altered fibrin variables.

Other Diseases

Sjøland et al reported alterations in fibrin backdrop in 22 patients on chronic peritoneal dialysis.¹³⁶ Patients with end-stage renal illness had fibrin clots that were less permeable and resistant to fibrinolysis.¹³⁶ Similar alterations in fibrin backdrop have been shown in end-stage renal disease patients on chronic hemodialysis.¹³⁷ During a 3-year follow-up, clots fabricated from baseline plasma taken from patients who died of cardiovascular causes were significantly less permeable and lysed less efficiently than those from plasma of the remaining patients,¹³⁷ indicating that altered fibrin backdrop may incur a worse prognosis in end-stage renal disease.

Patients with chronic obstructive pulmonary affliction displayed unfavorable, meaty, and poorly lysable fibrin structure, which could contribute to an increased chance of thrombotic events.¹³⁸ Jell permeability and lysis time in chronic obstructive pulmonary illness patients were associated with CRP, a marker of inflammation, which was a stronger predictor for fibrin structure in this study than fibrinogen concentration. CRP binds to fibrin(ogen) and thus may modify fibrin formation, although the mechanisms underlying such fibrin(ogen) modification are unknown.¹³⁹ In patients with advanced CAD, despite the presence of several clot-modifying run a risk factors, eg, diabetes, elevated CRP was associated with the formation of denser fibrin and resistance to lysis.¹¹⁵ Rheumatoid arthritis is another example of a chronic inflammatory affliction with a high adventure of MI, stroke, and VTE that associates with the formation of dense and poorly lysable clots.¹⁴⁰ Information technology is unclear whether effective therapy of rheumatoid arthritis associated with a marked reduction in CRP¹⁴¹ leads to improved fibrin characteristics.

Concluding Remarks

Fibrin clot structure and function are adamant by genetic and environmental factors, including cigarette smoking, inflammatory status, hyperglycemia, oxidative stress, and elevated Hcy levels. Atherothrombotic vascular disease and VTE represent a major crusade of morbidity and bloodshed worldwide. Growing bear witness supports the concept that fibrin characteristics may represent a novel risk factor for arterial and venous thromboembolism.

The associations between thrombosis and fibrin properties are reported largely in instance-control and cohort studies. Drugs constructive in cardiovascular prevention, especially aspirin and statins, can improve fibrin properties. It remains to be elucidated whether fibrin properties are vascular bed-specific and to what extent shear stress alters fibrin compages. Relative contributions of cellular and soluble factors modulating fibrin formation in various diseases are as well unknown. Prospective studies with long-term follow-upward are required to investigate whether fibrin parameters can predict an increased risk for thromboembolic events in the full general population and also in subjects with arterial or venous disease. Furthermore, the potential impact of prothrombotic fibrin phenotypes on progression of atherosclerosis and mechanisms involved in this process is besides of interest.

Many of the mechanisms that determine fibrin structure remain to exist elucidated. For instance, the mechanisms by which twisting, interconnected fibers and fiber bundles are formed from initial, pocket-sized protofibrils are only offset to exist understood. Once detailed mechanisms accept been determined, strategies to attune fibrin construction with new, specific agents may be developed and their office in thrombosis explored using in vitro and in vivo experimentation, followed by first-in-human studies. The relationships between fibrin viscoelastic backdrop, interactions with cells (platelets, erythrocytes, and leukocytes), blood menstruation, and thrombus stability are other areas for future study. Noesis of potential mechanisms involved in clot embolization is limited. Basic mechanisms that determine fibrin structure are only beginning to be understood, and many studies consistently report on altered fibrin structure in thrombosis. These findings hold the promise of hereafter developments of new strategies for the treatment of thrombosis that remain unaddressed with current anticoagulants and thrombolytics.

Sources of Funding

This work was supported by a grant of Jagiellonian University (No. Grand/ZDS/000565, to A.U.), the British Centre Foundation, the Medical Enquiry Council, and the Circulation Foundation (to R.A.).

Disclosures

None.

Footnotes

Correspondence to Robert A.Due south. Ariëns, PhD,

Segmentation of Cardiovascular and Diabetes Enquiry, Department on Mechanisms of Thrombosis, HT Laboratories, Clarendon Manner, University of Leeds, Leeds LS2 9JT, Uk

. Electronic mail r.a.southward. [email protected] air conditioning.uk

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