Altered Plasma Fibrin Clot Properties Are Associated With In-Stent Thrombosis

Undas, Anetta; Zalewski, J; Krochin, Marek; Siudak, Zbigniew; Sadowski, Marcin; Pręgowski, Jerzy; Dudek, Dariusz; Janion, Marianna; Witkowski, Adam; Żmudka, Krzysztof

doi:10.1161/atvbaha.109.194936

Cited by 55 publications

(52 citation statements)

References 29 publications

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“…[34][35][36] Ex vivo clots of patients with premature coronary artery disease are stiffer, form a denser fibrin network, Figures 3 and 4 show the responses for all tested concentrations, including the ka and kd fitting, which were used to determine the Kd values as presented in Table 2 7 Our experiments show that FXIIa changes fibrin clot structure in a dose-dependent manner. The effects of FXIIa on fibrin structure are consistent with those observed in patients with thrombosis.…”

Section: Discussionmentioning

confidence: 99%

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Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin

Konings

Govers‐Riemslag

Philippou

et al. 2011

Blood

120

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Recent data indicate an important contribution of coagulation factor (F)XII to in vivo thrombus formation. Because fibrin structure plays a key role in clot stability and thrombosis, we hypothesized that FXII(a) interacts with fibrin(ogen) and thereby regulates clot structure and function. In plasma and purified system, we observed a dose-dependent increase in fibrin fiber density and decrease in turbidity, reflecting a denser structure, and a nonlinear increase in clot stiffness with FXIIa. In plasma, this increase was partly independent of thrombin generation, as shown in clots made in prothrombindeficient plasma initiated with snake venom enzyme and in clots made from plasma deficient in FXII and prothrombin. Purified FXII and ␣-FXIIa, but not ␤-FXIIa, bound to purified fibrinogen and fibrin with nanomolar affinity. Immunostaining of human carotid artery thrombi showed that FXII colocalized with areas of dense fibrin deposition, providing evidence for the in vivo modulation of fibrin structure by FXIIa. These data demonstrate that IntroductionBlood coagulation culminates in the formation of fibrin, which binds platelets and forms a clot. Fibrin is formed from fibrinogen via cleavage of 2 fibrinopeptides from the A␣-and B␤-chains N-termini, located in the E-region, by thrombin. 1 Fibrinopeptide cleavage exposes binding sites for complementary sites in the D-region, triggering polymerization and the production of protofibrils. Protofibrils aggregate laterally to form fibers, which branch out and form a 3-dimensional network. 2 There is increasing evidence that the structure of fibrin regulates thrombosis. Dense fibrin clots with small pores and increased fiber density are more resistant to lysis. 3 Structural characteristics affect the mechanical properties of fibrin. 4 Both venous and arterial thrombosis has been associated with the formation of an altered fibrin network. [5][6][7][8][9][10] The role of factor (F)XII in hemostasis has long been contested because deficiency in FXII, unlike deficiencies of other coagulation factors, does not lead to bleeding diathesis in humans 11 or in mice. 12 However, recent in vivo data show that FXII deficiency or inhibition in rodent models reduces thrombus formation while maintaining normal hemostasis. [12][13][14][15] These findings indicate the existence of FXII-related mechanisms that are preferentially involved in thrombosis but not hemostasis.Contact activation is triggered by the binding of FXII (80 kDa) to a negatively charged surface and involves the formation of ␣-FXIIa via autocatalysis. Bound ␣-FXIIa converts prekallikrein into kallikrein. Kallikrein can further convert ␣-FXIIa to ␤-FXIIa by an additional cleavage at R334-N335. ␣-FXIIa consists of a heavy and light chain that are disulphide linked (80 kDa), whereas ␤-FXIIa (28 kDa) lacks the heavy chain and loses its capacity to bind to negatively charged surfaces. 16 The N-terminal region of FXII (␣-FXIIa heavy chain) shows strong homology with tissuetype plasminogen activator (tPA), with the presence of fibr...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin

Konings

Govers‐Riemslag

Philippou

et al. 2011

Blood

120

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“…120 Fibrin clot properties have been implicated in 2 lifethreatening 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 clot 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 structure.…”

Section: Cadmentioning

confidence: 99%

“…Patients with stent thrombosis showed a more tightly packed and less porous fibrin structure. 121 These alterations could prolong the presence of fibrin in the lumen. Interestingly, these findings indicate that apart from other factors associated with stent thrombosis (including the procedure itself, patient and lesion characteristics, stent design, and premature cessation of antiplatelet drugs), fibrin-related factors might contribute not only to late thrombosis but also acute and subacute stent thrombosis, in particular when stent malapposition or underexpansion are excluded.…”

Section: Cadmentioning

confidence: 99%

Fibrin Clot Structure and Function

Undas

Ariëns

2011

ATVB

Self Cite

437

200

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Abstract-The formation of fibrin clots that are relatively resistant to lysis represents the final step in blood coagulation. We discuss the genetic and environmental regulators of fibrin structure in relation to thrombotic disease. In addition, we discuss the implications of fibrin structure for treatment of thrombosis. Fibrin clots composed of compact, highly branched networks with thin fibers are resistant to lysis. Altered fibrin structure has consistently been reported in patients with several diseases complicated by thromboembolic events, including patients with acute or prior myocardial infarction, ischemic stroke, and venous thromboembolism. Relatives of patients with myocardial infarction or venous thromboembolism display similar fibrin abnormalities. Low-dose aspirin, statins, lowering of homocysteine, better diabetes control, smoking cessation, and suppression of inflammatory response increase clot permeability and susceptibility to lysis. Growing evidence indicates that abnormal fibrin properties represent a novel risk factor for arterial and venous thrombotic events, particularly of unknown etiology in young and middle-aged patients. (Arterioscler Thromb Vasc Biol. 2011;31:e88-e99.)

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“…Recent studies have focused more on the clot by measuring fibre qualities, clot strength, porosity and lyzability [43].…”

Section: Phenotypementioning

confidence: 99%

Introduction to haemostasis from a pharmacodynamic perspective

Kluft

Burggraaf

2011

Brit J Clinical Pharma

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Biochemical characterization of the haemostatic system has advanced significantly in the past decades. Sub-systems, such as coagulation, fibrinolysis, blood cells and platelets and the vessel wall have been studied by specialists, mostly separately and independently. The time has come to integrate the approaches, and, in particular, to develop tests to document the state of the whole system and to have available adequate pharmacodynamic tests to evaluate treatments. Many examples are available to show that traditional general methods of clotting and lysis do not provide the information that is desired. The present tendency is to use specific methods for specific factors or effects which are very limited in pharmacological information. There is also increasing awareness of the occurrence of rather broad interindividual variability in the haemostatic system. This suggests that individually tailored treatments are required. This is the more relevant since haemostasis is a balance and treatment should be positioned between efficacy and safety. The conclusion is reached that there is a need for integrated or global methods or sets of methods that reflect the complexity and individual status appropriately and allow the practitioner to judge the effects of interventions and their individual aspects. IntroductionMaintenance of blood fluidity within the vascular system is an important physiological theme. At the same time, the local formation of a clot serves to assist in preventing excessive blood leakages, and in aiding tissue repair. In addition clot formation is involved in host defence.A balance with, on the one hand, a deviation in excessive clot formation and, on the other hand, defective clot formation was proposed originally by Astrup in 1958 [1]. The system requires delicate biochemical regulation to maintain this balance and to serve the various functions adequately.Deviations in the haemostasis of excessive clot formation or thrombosis are involved in arterial diseases such as myocardial infarction and ischaemic stroke, in venous diseases such as deep vein thrombosis and pulmonary embolism, and in organ failure during trauma and infections.This is a major cause of death and disabilities. Another deviation concerns defects in clot formation and subsequent bleeding, known from congenital deficiencies in clotting factors such as factor VIII and IX, but also potentially life threatening during trauma and a major issue in critical care medicine.Many treatment options to reinforce the system or to inhibit parts of it have been developed and are still under active development. These treatments inevitably interfere with the balance mentioned earlier and besides the intended effect, the opposite effect (bleeding or thrombosis) is always associated with the treatments as a safety issue.The present introduction evaluates recent developments in concepts in haemostasis, the status of biomarker analysis and the desired development of pharmacodynamic tests. Development of concepts Biochemical conceptsHaemostasis is regulate...

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Altered Plasma Fibrin Clot Properties Are Associated With In-Stent Thrombosis

Cited by 55 publications

References 29 publications

Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin

Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin

Fibrin Clot Structure and Function

Introduction to haemostasis from a pharmacodynamic perspective

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