Fibrinogen Naples I (Bβ A68T) Nonsubstrate Thrombin-Binding Capacities

Meh, David A.; Mosesson, Michael W.; Siebenlist, Kevin R.; Simpson-Haidaris, Patricia J.; Brennan, Stephen O.; DiOrio, James P.; Thompson, Kevin J.; Minno, G. Di

doi:10.1016/s0049-3848(01)00273-0

Cited by 28 publications

(48 citation statements)

References 39 publications

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“…(Table I). Thus, the affinity of ␣-IIa for ␥ A /␥ A -fibrin was reduced 3.4-fold when the ␤15-42 sequence was removed, consistent with the concept that this sequence represents at least part of the low affinity thrombinbinding site on ␥ A /␥ A -fibrin (16,40). Although the affinity of ␣-IIa for des-␤15-42-␥ A /␥Ј-fibrin was 2. reduction in affinity of ␣-IIa for des-␤15-42-␥ A /␥Ј-fibrin was verified using 125 I-FPR-␣-IIa, where the Scatchard plot reveals a single class of binding sites (Fig.…”

Section: Resultssupporting

confidence: 72%

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Evidence That Both Exosites on Thrombin Participate in Its High Affinity Interaction with Fibrin

Pospisil

Stafford

Fredenburgh

et al. 2003

Journal of Biological Chemistry

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Section: Resultssupporting

confidence: 72%

“…When clotted, fibrinogen Naples I (B␤ A68T) exhibits reduced affinity of both high and low affinity binding interactions (40). These findings suggest that attenuation of exosite 1-mediated interaction with the mutant NH 2 terminus of the ␤-chain impairs high affinity binding mediated by the ␥Ј-chain.…”

Section: Discussionmentioning

confidence: 99%

Evidence That Both Exosites on Thrombin Participate in Its High Affinity Interaction with Fibrin

Pospisil

Stafford

Fredenburgh

et al. 2003

Journal of Biological Chemistry

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“…47 The result of these differences is that clots with thinner fibrin fibers might bind less thrombin at the wound site than "normal" clots. It is difficult to say, however, what the physiologic impact of altered thrombin binding is, because both clot-bound thrombin [48][49][50] as well as decreased binding of thrombin to clots 51,52 have been correlated with procoagulant activity and thrombosis. Nonetheless, these observations suggest that there is an "optimum thrombin concentration" that forms an "optimum clot structure," and that deviation from this optimum structure can result in dysregulation of hemostasis and recurrent thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk

Wolberg

Monroe

Roberts

et al. 2003

Blood

150

138

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Individuals with elevated prothrombin levels are at increased risk of venous thrombosis. To understand the mechanism behind this observation, we studied the effect of prothrombin concentration on thrombin generation and fibrin clot structure. The pattern of thrombin generation was directly related to the prothrombin level at all concentrations tested. From 0% to 300% of normal plasma levels of prothrombin, increasing the prothrombin concentration increased the initial rate, peak, and total amount of thrombin generated. Importantly, fibrin clot structure was also affected by the prothrombin concentration. Fibrin clots made from prothrombin concentrations less than 10% of plasma levels were weak and poorly formed. Fibrin clots made at 10% to 100% of plasma levels of prothrombin had similar fiber structures (mass-to-length ratio; ). However, the fiber mass-tolength ratio decreased with increasing prothrombin levels more than 100% of plasma levels, in a dose-dependent manner. These results suggest that increased levels of prothrombin alter thrombin generation and clot structure. Specifically, elevated prothrombin levels produce clots with reduced fibrin mass-to-length ratios compared with normal clots. We hypothesize that this alteration in fibrin clot structure is an important determinant of the risk of thrombosis. IntroductionElevated levels of several coagulation factors, including factors XI, 1 VIII:C, 2 and fibrinogen, 3,4 have been correlated with an increased risk of thrombosis in epidemiologic studies. Recently, elevated levels of prothrombin have also been correlated with a risk of arterial and venous thrombosis. [5][6][7] A mutation in the 3Ј-untranslated region of the prothrombin coding gene has been described, which is related to the elevated levels of prothrombin. 5 However, the mechanism by which elevated prothrombin contributes to thrombosis is thus far unresolved.The increased tendency of patients with elevated prothrombin to experience thrombosis does not appear to result from an increased level of ongoing hemostatic activation; prothrombin fragment 1 ϩ 2 levels are not constitutively elevated in these patients. 8 Kyrle et al, however, observed a significantly increased endogenous thrombin potential in both heterozygous and homozygous carriers of the 20210GϾA mutation, 8 suggesting that elevated levels of prothrombin result in increased thrombin generation during coagulation events. In vitro models of coagulation support this hypothesis. Several studies have shown that increasing the initial level of prothrombin affects several parameters of thrombin generation, including the initial rate of thrombin generation and total amount of thrombin generated. 9,10 Even moderate increases in the prothrombin level (to 150% of normal plasma levels) results in a substantial increase (71%-121%) in the amount of thrombin generated in vitro. 9 Increased thrombin generation, by itself, however, does not provide a direct biochemical mechanism for the increased risk of thrombosis. That is, the increased thrombin must...

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“…Different mechanisms may account for the increased risks of thrombosis in dysfibrinogenemia, including elevated levels of circulating thrombin resulting from the failure in fibrinogen binding,21 altered strength, architecture and stability of the fibrin network22 and decreased fibrinolysis resulting from impaired binding of plasminogen or tPA to abnormal fibrinogen 23. Fibrin has an appreciable thrombin-binding potential and was termed antithrombin I,24 and the N-terminal portions of Aα chain (Aα 46–69) and Bβ chain (Bβ 35–62) are the low-affinity thrombin-binding sites in fibrin 13 25.…”

Section: Discussionmentioning

confidence: 99%

Dysfibrinogenemia-associated novel heterozygous mutation, Shanghai (FGAc.169_180+2 del), leads to N-terminal truncation of fibrinogen Aα chain and impairs fibrin polymerization

Zhou

Ding

et al. 2016

J Clin Pathol

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Fibrinogen Naples I (Bβ A68T) Nonsubstrate Thrombin-Binding Capacities

Cited by 28 publications

References 39 publications

Evidence That Both Exosites on Thrombin Participate in Its High Affinity Interaction with Fibrin

Evidence That Both Exosites on Thrombin Participate in Its High Affinity Interaction with Fibrin

Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk

Dysfibrinogenemia-associated novel heterozygous mutation, Shanghai (FGAc.169_180+2 del), leads to N-terminal truncation of fibrinogen Aα chain and impairs fibrin polymerization

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