Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin

Dupuy, Évelyne; Soria, Claudine; Molho, P; Zini, Jean‐Marc; Rosenstingl, S.; Laurian, Claude; Bruneval, Patrick; Tobelem, Gérard

doi:10.1016/s0049-3848(01)00247-x

Cited by 88 publications

(110 citation statements)

References 26 publications

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“…46 A low-affinity interaction between ABE I and the fibrin E domain facilitates a high-affinity interaction between ABE II and fibrin ␥Ј chains, down-regulating ␣-IIa activity. Loss of antithrombin I activity has been implicated in thrombotic episodes in patients with afibrinogenemia 47,48 and some dysfibrinogenemias. 49 ␤-IIa and ␥-IIa are probably less susceptible to antithrombin I activity, partly explaining their potency in the thrombin generation assay.…”

Section: Discussionmentioning

confidence: 99%

Activation of factor XI by products of prothrombin activation

Matafonov

Sarilla

Sun

et al. 2011

Blood

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The prothrombinase complex converts prothrombin to ␣-thrombin through the intermediate meizothrombin (Mz-IIa). Both ␣-thrombin and Mz-IIa catalyze factor (F) XI activation to FXIa, which sustains ␣-thrombin production through activation of FIX. The interaction with FXI is thought to involve thrombin anion binding exosite (ABE) I. ␣-Thrombin can undergo additional proteolysis to ␤-thrombin and ␥-thrombin, neither of which have an intact ABE I. In a purified protein system, FXI is activated by ␤-thrombin or ␥-thrombin, and by ␣-thrombin in the presence of the ABE I-blocking peptide hirugen, indicating that a fully formed ABE I is not absolutely required for FXI activation. In a FXI-dependent plasma thrombin generation assay, ␤-thrombin, ␥-thrombin, and ␣-thrombins with mutations in ABE I are approximately 2-fold more potent initiators of thrombin generation than ␣-thrombin or Mz-IIa, possibly because fibrinogen, which binds to ABE I, competes poorly with FXI for forms of thrombin lacking ABE I. In addition, FXIa can activate factor FXII, which could contribute to thrombin generation through FXIIa-mediated FXI activation. The data indicate that forms of thrombin other than ␣-thrombin contribute directly to feedback activation of FXI in plasma and suggest that FXIa may provide a link between tissue factorinitiated coagulation and the proteases of the contact system. (Blood. 2011;118(2): 437-445) IntroductionThe trypsin-like protease ␣-thrombin (␣-IIa) is a key contributor to vital host responses to injury, including fibrin formation, 1-3 platelet and endothelial cell activation, 4 and inflammation. 5 During coagulation, prothrombin is converted to ␣-IIa through a series of proteolytic steps catalyzed by factor (F) Xa. 6,7 The process results in formation of a functional active site and expression of 2 anion binding exosites (ABE I and ABE II) that are required for ␣-IIa interactions with many substrates, receptors, and inhibitors (Table 1). [1][2][3]6 In the presence of FVa and phospholipid, FXa initially converts prothrombin to the protease meizothrombin (Mz-IIa; Figure 1A), 7-11 which expresses ABE I. 6 Mz-IIa is rapidly converted to ␣-IIa, which may undergo further proteolysis to form ␤-thrombin (␤-IIa) and ␥-thrombin (␥-IIa) ( Figure 1B), 2 proteases with reduced capacity to catalyze ABE I-dependent reactions. [9][10][11][12] Physiologic roles for ␤-IIa or ␥-IIa have not been established; however, both have been identified in clotting blood. 11 ␣-IIa up-regulates its own generation by activating the cofactors FV and FVIII, [1][2][3]9 and by converting FXI to the protease FXIa. 13,14 FXIa, in turn, sustains ␣-IIa generation by converting FIX to FIXa␤, 15 and possibly by activating FV and FVIII. 16 In the original cascade/ waterfall hypotheses of coagulation, FXI is activated by FXIIa 17,18 ; however, current models deemphasize this reaction based on the observation that FXI deficiency is associated with abnormal bleeding, whereas FXII deficiency is not. 18 FXI activation by ␣-IIa would explain the phenotypic di...

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Section: Discussionmentioning

confidence: 99%

Activation of factor XI by products of prothrombin activation

Matafonov

Sarilla

Sun

et al. 2011

Blood

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“…Paradoxically both arterial and venous thromboembolic complications have been reported in afibrinogenemic patients [Cronin et al, 1988;Dupuy et al, 2001;Girolami et al, 2006]. These complications can occur in the presence of concomitant risk factors such as a coinherited thrombophilic risk factor [De Mattia et al, 1993] or after replacement therapy.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…One has to remember that even in the absence of fibrinogen platelet aggregation is possible due to the action of von Willebrand factor [De Marco et al, 1986] and, in contrast to hemophiliacs, afibrinogenemic patients can generate thrombin, in both the initial phase of limited production but also the secondary burst of thrombin generation [Roberts et al, 1998]. In some patients increase of prothrombin activation fragments or thrombin-antithrombin complexes has been observed, which may reflect an enhanced thrombin generation [Dupuy et al, 2001;Korte and Feldges, 1994]. Interestingly, an anti-thrombin role has also been attributed to fibrinogen, since in its absence the clearance of thrombin is impaired [de Bosch et al, 2002].…”

Section: Clinical Featuresmentioning

confidence: 99%

“…Plasma activity of all other clotting factors is normal. Some abnormalities in platelet functions tests can be observed , which can be reversed upon addition of fibrinogen [Dupuy et al, 2001]. Since fibrinogen is one of the main determinants of erythrocyte sedimentation rate, it is not surprising that afibrinogenemic patients have very low erythrocyte sedimentation rates.…”

Section: Laboratory Abnormalitiesmentioning

confidence: 99%

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Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

Neerman-Arbez

Moerloose

2007

Hum. Mutat.

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Communicated by Arupa GangulyFibrinogen is synthesized in hepatocytes in the form of a hexamer composed of two sets of three polypeptides (Aa, Bb, and c). Each polypeptide is encoded by a distinct gene, FGA, FGB, and FGG, all three clustered in a region of 50 kb on 4q31. Congenital afibrinogenemia is characterized by the complete absence of fibrinogen, the precursor of the major protein constituent of the blood clot, fibrin. Although the disease was first described in 1920, the genetic defect responsible for this disorder long remained unknown. We identified the gene and the first causative mutations for this disease in a nonconsanguineous Swiss family in 1999. Since this first report, 61 additional mutations, the majority in FGA, have been identified in patients with afibrinogenemia (in homozygosity or in compound heterozygosity) or in heterozygosity in hypofibrinogenemia, since many of these patients are in fact asymptomatic carriers of afibrinogenemia mutations. Mutations in the fibrinogen genes may lead to deficiency of fibrinogen by several mechanisms: these can act at the DNA level, at the RNA level by affecting mRNA splicing or stability, or at the protein level by affecting protein synthesis, assembly, or secretion. The expression of selected mutations has shown that mechanisms acting at all three levels play a role in the molecular basis of this disease. We report here the identification of 10 novel mutations, of which eight are localized in FGA, thus increasing the total number of causative mutations identified to 72 and confirming the relative importance of FGA in the molecular basis of fibrinogen deficiency. Hum Mutat 28(6), [540][541][542][543][544][545][546][547][548][549][550][551][552][553] 2007. r r 2007 Wiley-Liss, Inc.

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“…We are concerned that the recommendation to maintain high levels of fibrinogen may have played a role in the development of paradoxical thromboses. Patients with afibrinogenemia have been reported to have had both arterial and venous thrombosis, with and without prior infusion of fibrinogen, and with and without underlying tendencies to thrombophilia [7].…”

Section: Discussionmentioning

confidence: 99%

Pregnancy‐related thrombosis in a woman with congenital afibrinogenemia: A report of two successful pregnancies

et al. 2004

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We managed two pregnancies in a woman with congenital afibrinogenemia with increasing amounts of cryoprecipitate to achieve a pre-infusion fibrinogen level of 60 mg/dL. The first pregnancy resulted in placental abruption at 36 weeks, in spite of recent cryoprecipitate infusion. Both placentas showed infarction. Post-partum ovarian and renal vein thromboses complicated the second pregnancy. Mean FVIII (344%) and vWF Antigen (323%) were elevated prior to cryoprecipitate infusion, with mean post-infusion levels of 367% and 363%. The clearance of fibrinogen after cryoprecipitate infusion increased during the course of pregnancy. A paradoxical prothrombotic state with embolization may play a role in the observed complications of pregnancy. Am.

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Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin

Cited by 88 publications

References 26 publications

Activation of factor XI by products of prothrombin activation

Activation of factor XI by products of prothrombin activation

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

Pregnancy‐related thrombosis in a woman with congenital afibrinogenemia: A report of two successful pregnancies

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