The Prevalence of Factor XII Deficiency in 103 Orally Anticoagulated Outpatients Suffering from Recurrent Venous and/or Arterial Thromboembolism

Halbmayer, Walter‐Michael; Mannhalter, Christine; Feichtinger, C; Rubi, K; Fischer, Michael B.

doi:10.1055/s-0038-1656366

Cited by 115 publications

(70 citation statements)

References 23 publications

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“…Both prekallikrein and HK deficiencies are too rare to allow us to draw firm conclusions. However, there is an increased incidence of thrombosis in patients with congenital homozygous factor XII deficiency [33][34][35][36][37] and an increased incidence of congenital factor XII deficiency in patients with venous thrombosis and acquired thrombotic disorders such as myocardial infarction 38 and restenosis of common arteries after thrombolytic therapy. 39 The clinical relevance of kininogen deficiency is as yet undefined.…”

Section: Discussionmentioning

confidence: 99%

Kininogens Are Antithrombotic Proteins In Vivo

Colman

White

Scovell

et al. 1999

ATVB

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Abstract-Kininogens have recently been shown to possess antiadhesive, anticoagulant, and profibrinolytic properties and can inhibit platelet activation at low thrombin concentrations. To test whether kininogens have antithrombotic properties in vivo, we devised a model of limited arterial injury confined to removal of the endothelium. Brown-Norway Katholiek strain rats with an absence of low-and high-molecular-weight kininogen due to a single point mutation, A163T, were compared in the thrombosis model to the wild-type animals, which were otherwise genetically identical. Despite an equivalent vascular injury, the mean time (ϮSEM) for a 90% decrease in flow measured by laser Doppler was 38.4Ϯ17 minutes in the kininogen-deficient rats compared with 194Ϯ29 minutes in the wild-type animals (PϽ0.002). Key Words: arterial thrombosis Ⅲ kininogens Ⅲ antithrombotic Ⅲ fibrinolysis Ⅲ rats K ininogens are plasma proteins first recognized as the precursors of a peptide, bradykinin, which was liberated by plasma kallikrein. 1 Bradykinin can reproduce many inflammatory changes, including edema, pain, vasodilation, and increased vascular permeability. A deficiency of plasma high-(HK) and low-(LK) molecular-weight kininogens 2 in humans does not lead to a hemorrhagic disorder, despite a marked prolongation of the activated partial thromboplastin time. In fact, cloning 3 and delineation of the structurefunction relationships of kininogen have revealed new properties of this protein, including cysteine protease inhibition, 4 modulation of thrombin-induced platelet aggregation, 5 antiadhesive properties, 6 and profibrinolytic potential. 7 HK and LK have been divided into domains D1, D2, and D3, which compose the common heavy-chain N-terminal to domain D4, which contains the bradykinin sequence. LK contains a small domain, D5 L , whereas HK contains the large domains D5 H and D6, which compose the light chains. 3 The ability of D2 of the kininogens to inhibit platelet calpain 4 has been linked to an inhibition of thrombin-induced platelet aggregation, 8 whereas inhibition of the binding of thrombin to platelets by D3 of kininogens has led to a 10-fold shift in the doseresponse curve of thrombin-induced platelet activation. 9 HK can compete for fibrinogen binding to neutrophils 10 by competing for a site on the integrin Mac-1 11 and thus, limit the adhesion of neutrophils to artificial and biological surfaces. Peptides from D6 of HK can downregulate urokinasedependent plasminogen activation on human endothelial cells 7 by inhibiting the binding of prekallikrein to HK.All of these studies suggest that HK should serve as an antithrombotic protein. Conversely, individuals deficient in HK should manifest a prothrombotic state. Unfortunately, HK deficiency is a rare condition, and only a very small number of individuals have been observed in a serial fashion. Therefore, to test this hypothesis, we decided to use a well-defined animal model. Fortunately, a natural "knockout" exists in the Katholiek strain of the Brown-Norway rat. These rat...

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Section: Discussionmentioning

confidence: 99%

Kininogens Are Antithrombotic Proteins In Vivo

Colman

White

Scovell

et al. 1999

ATVB

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“…A hypercoagulable state in sickle cell disease and betathalassemia is well documented [1,2]. Factor V (FV) Leiden is the largest inherited risk factor of venous thrombosis [3].…”

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The 46C→T polymorphism in the factor XII gene (F12) and the risk of venous thrombosis

Bertina

Poort

Vos

et al. 2005

Journal of Thrombosis and Haemostasis

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The 46CfiT polymorphism in the factor XII gene (F12) and the risk of venous thrombosis The precise role of factor XII (FXII) in the regulation of blood coagulation and fibrinolysis is still undefined. Activation of FXII initiates both the kinin-forming cascade and the intrinsic coagulation and fibrinolytic pathways. Subjects with severe FXII deficiency show a prolonged activated partial thromboplastin time but do not have a bleeding tendency, which suggests a minor role for FXII in the regulation of fibrin formation in vivo. The observation that FXII is also involved in the activation of the fibrinolytic system led to the hypothesis that partial or severe FXII deficiency might result in impaired fibrinolysis and as a consequence in a thrombotic tendency. Indeed, a high frequency (9-15%) of reduced plasma FXII levels was found among patients with (venous) thrombosis [1,2] and women with recurrent miscarriages [3], a condition often associated with a thrombophilic state. However, Koster et al. R . M . B E R T I N A , * S . R . P O O R T , * H . L . V O S * and F . R . R O S E N D

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“…Coagulation factor XII (FXII, Hagemann factor) plays a central role in the initiation of coagulation and fibrinolysis, but its physiological role is still under discussion. Some studies reported a correlation between FXII levels and the prevalence of venous thrombosis [3,4] but others did not find reduced FXII levels among thrombosis patients [5,6].…”

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The functional -4C>T polymorphism of the coagulation factor XII gene is not associated with deep venous thrombosis

Grünbacher¹,

Marx-Neuhold²,

Pilger

et al. 2005

Journal of Thrombosis and Haemostasis

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9 Maccarana M, Lindahl U. Mode of interaction between platelet factor 4 and heparin. The functional -4C>T polymorphism of the coagulation factor XII gene is not associated with deep venous thrombosis Deep venous thrombosis (DVT) is a common multicausal disease. The etiology of DVT includes both environmental and genetic factors [1,2]. Coagulation factor XII (FXII, Hagemann factor) plays a central role in the initiation of coagulation and fibrinolysis, but its physiological role is still under discussion. Some studies reported a correlation between FXII levels and the prevalence of venous thrombosis [3,4] but others did not find reduced FXII levels among thrombosis patients [5,6].A common C>T polymorphism four nucleotides upstream of the start codon of the FXII gene (F12 -4C>T, NCBI SNP ID rs17876008) has been associated with lower FXII levels [7][8][9][10]. This polymorphism has previously been described as 46C>T based upon the numbering from the beginning of the transcription, but this notation does not conform to recommendations for human gene mutation nomenclature [11] and will not be used in this study. The T variant lacks a Kozak consensus sequence, resulting in a decreased translational efficiency and lower FXII plasma levels [7]. Tirado et al. [8] suggested the -4 C>T polymorphism as a genetic risk factor for DVT, but a larger subsequent study failed to find an association between that polymorphism and DVT [6]. The aim of our study was therefore to investigate the potential association of this polymorphism with DVT.Three hundred and forty six subjects with a documented episode of DVT admitted to the Division of Angiology of the Department of Internal Medicine, Medical University Graz, between December 1997 and November 1999, were enrolled as the patient group. DVT was diagnosed by ultrasonography and/or venography. A control group of similar age and sex distribution was selected from patients of the same department (n ¼ 352). Subjects were eligible as controls if they were without a history of venous (DVT, pulmonary embolism, primary varicosis) or arterial disease (coronary heart disease, cerebrovascular disease, peripheral arterial occlusive disease). The study was approved by the local ethics committee and all individuals participating in the study gave their informed consent. All subjects were Austrian and of Caucasian ethnicity.Isolation of genomic DNA and detection of prothrombin (F2 20210G>A) and factor V Leiden (F5 R506Q) genotypes were generated as described previously [12]. The F12 -4C>T polymorphism was determined by a TaqMan TM fluorogenic 5¢-nuclease assay (Applied Biosystems, Vienna, Austria) using Applera's Assays-by-Design custom service.Sequences of primers and probes were as follows: forward primer (5¢-GGATAGGCAGCTGGACCAA-3¢), reverse primer (5¢-CCAAGCTCACCAGCAGGAA-3¢), C-probe (5¢-VIC-CTCATGGCGTCCGTC-NFQ-3¢), and T-probe (5¢-FAM-CTCATGGCATCCGTC-NFQ-3¢). Statistical analysis was performed using SPSS 11.0.1 for Windows. Metric values were analyzed by Student's t-test and presented as mean ...

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The Prevalence of Factor XII Deficiency in 103 Orally Anticoagulated Outpatients Suffering from Recurrent Venous and/or Arterial Thromboembolism

Cited by 115 publications

References 23 publications

Kininogens Are Antithrombotic Proteins In Vivo

Kininogens Are Antithrombotic Proteins In Vivo

The 46C→T polymorphism in the factor XII gene (F12) and the risk of venous thrombosis

The functional -4C>T polymorphism of the coagulation factor XII gene is not associated with deep venous thrombosis

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