Heritability of Clot Formation

Standeven, Kristina F.; Willige, Shirley Uitte de; Carter, Angela M.; Grant, Peter J.

doi:10.1055/s-0029-1234141

Cited by 17 publications

(9 citation statements)

References 69 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: 95%

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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: 95%

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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“…It has been established that genetic factors explain 10–50% of variance in fibrin clot measures [16]. About 25% of rare congenital dysfibrinogenemias resulting from mutations in all three fibrinogen genes, despite low levels of functional fibrinogen measured using the Clauss assay, are linked with VTE and at least some of them are known to significantly alter fibrin clot structure [17].…”

Section: Modifiers Of Fibrin Clot Propertiesmentioning

confidence: 99%

Prothrombotic Fibrin Clot Phenotype in Patients with Deep Vein Thrombosis and Pulmonary Embolism: A New Risk Factor for Recurrence

Undas

2017

BioMed Research International

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Prothrombotic fibrin clot phenotype, involving faster formation of dense meshwork composed of thinner and highly branched fibers that are relatively resistant to plasmin-induced lysis, has been reported in patients with not only myocardial infarction or stroke, but also venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT), and/or pulmonary embolism (PE). Prothrombotic fibrin clot phenotype, in particular prolonged clot lysis time, is considered a novel risk factor for VTE as well as venous thrombosis at unusual location, for example, cerebral sinus venous thrombosis, retinal vein obstruction, and Budd-Chiari syndrome. Growing evidence from observational studies indicates that abnormal fibrin clot properties can predict recurrent DVT and PE and they are involved in serious complications of VTE, for example, thromboembolic pulmonary hypertension and postthrombotic syndrome. The purpose of this article is to review our current understanding of the role of fibrin clot structure and function in venous thrombosis with emphasis on clinical issues ranging from prognosis to therapy.

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“…36 For most fibrin characteristics, heritability ranges from 10% to 40%. 34,37 Each fibrinogen chain is encoded by a separate gene, all 3 of which are located in the same region on chromosome 4 (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 ␤-chain incorporation as rate-limiting step.…”

Section: Genetic Factorsmentioning

confidence: 99%

Fibrin Clot Structure and Function

Undas

Ariëns

2011

ATVB

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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Heritability of Clot Formation

Cited by 17 publications

References 69 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

Prothrombotic Fibrin Clot Phenotype in Patients with Deep Vein Thrombosis and Pulmonary Embolism: A New Risk Factor for Recurrence

Fibrin Clot Structure and Function

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