scholarly journals A hitherto undescribed plasma factor acting at the contact phase of blood coagulation (Flaujeac factor): case report and coagulation studies

Blood ◽  
1975 ◽  
Vol 46 (5) ◽  
pp. 761-768 ◽  
Author(s):  
MJ Lacombe ◽  
B Varet ◽  
JP Levy
Keyword(s):  
Blood Coagulation ◽  
Coagulation Factor ◽  
Old French ◽  
Bleeding Tendency ◽  
Contact Phase ◽  
Hageman Factor ◽  
Coagulation Defect ◽  
Plasma Factor ◽  
Fletcher Factor

This paper reports an asymptomatic coagulation defect responsible for an abnormality at the contact phase of blood coagulation in vitro, distinct from Hageman factor and Fletcher factor deficiencies. Coagulation studies in a 50-yr-old French woman without bleeding tendency revealed the following results: whole-blood clotting time in glass tubes and activated partial thromboplastin time with kaolin and ellagic acid were greatly prolonged; one-stage prothrombin was normal; no circulating anticoagulant was detected, and the infusion of normal plasma corrected the coagulation defect with an estimated half-life of 6.5 days; the levels of factor VIII, IX, XI, and XII were normal; mutual correction was obtained with a Fletcher factor-deficient plasma; the level of whole complement was normal. Studies of the contact phase of blood coagulation and contact-induced fibrinolysis showed the same abnormalities as in Hageman factor- and Fletcher-deficient plasmas. These results indicate that the patient's plasma is deficient in a previously undescribed coagulation factor, which participates in the initial stage of the blood coagulation process in vitro. Family studies revealed consanguinity in the propositus' parents. The assay of this newly described factor in the propositus' children revealed a partial defect, compatible with a heterozygous state, in three of the four tested children. This indicates a recessive inheritance of this new blood coagulation defect.

A hitherto undescribed plasma factor acting at the contact phase of blood coagulation (Flaujeac factor): case report and coagulation studies

Blood ◽  
1975 ◽  
Vol 46 (5) ◽  
pp. 761-768 ◽  
Author(s):  
MJ Lacombe ◽  
B Varet ◽  
JP Levy
Keyword(s):  
Blood Coagulation ◽  
Coagulation Factor ◽  
Old French ◽  
Bleeding Tendency ◽  
Contact Phase ◽  
Hageman Factor ◽  
Coagulation Defect ◽  
Plasma Factor ◽  
Fletcher Factor

Abstract This paper reports an asymptomatic coagulation defect responsible for an abnormality at the contact phase of blood coagulation in vitro, distinct from Hageman factor and Fletcher factor deficiencies. Coagulation studies in a 50-yr-old French woman without bleeding tendency revealed the following results: whole-blood clotting time in glass tubes and activated partial thromboplastin time with kaolin and ellagic acid were greatly prolonged; one-stage prothrombin was normal; no circulating anticoagulant was detected, and the infusion of normal plasma corrected the coagulation defect with an estimated half-life of 6.5 days; the levels of factor VIII, IX, XI, and XII were normal; mutual correction was obtained with a Fletcher factor-deficient plasma; the level of whole complement was normal. Studies of the contact phase of blood coagulation and contact-induced fibrinolysis showed the same abnormalities as in Hageman factor- and Fletcher-deficient plasmas. These results indicate that the patient's plasma is deficient in a previously undescribed coagulation factor, which participates in the initial stage of the blood coagulation process in vitro. Family studies revealed consanguinity in the propositus' parents. The assay of this newly described factor in the propositus' children revealed a partial defect, compatible with a heterozygous state, in three of the four tested children. This indicates a recessive inheritance of this new blood coagulation defect.

Platelets and Factor XI Bypass the Contact System of Blood Coagulation

1999 ◽  
Vol 82 (08) ◽  
pp. 234-242 ◽  
Author(s):  
Peter Walsh
Keyword(s):  
Blood Coagulation ◽  
Coagulation Factor ◽  
Bleeding Complications ◽  
Ashkenazi Jews ◽  
Factor Xi ◽  
Contact Phase ◽  
Platelet Factor ◽  
Proteolytic Activation ◽  
Factor Xi Deficiency ◽  
Plasma Factor

IntroductionFactor XI is a plasma glycoprotein (concentration ∼30 nM) that was first identified by Rosenthal et al1 as a plasma coagulation factor deficiency in patients with abnormal hemostasis, particularly common among Ashkenazi Jews.2,3 In spite of recent advances in our understanding of the structure of factor XI and its gene, the structure-function relationships of the protein, and the molecular genetics of factor XI deficiency, considerable confusion about the physiologic role and clinical relevance of factor XI has arisen from both clinical and biochemical observations. One problem arises from the fact that, until recently, the only known pathway for activation of factor XI involved proteolytic activation by factor XIIa and interactions with coagulation proteins of the contact phase of blood coagulation.4-7 The problem arose from the clinical observation that patients with deficiencies of factor XI are subject to bleeding complications, whereas patients with deficiencies of the contact proteins are not.2,3,8-13 A related unanswered question concerns the lack of correlation in many reported patients between plasma levels of factor XI and the severity of clinical bleeding manifestations.2,3,8,9,13-15 In addition, some patients with severe factor XI deficiency experience significant bleeding complications, whereas others appear to be hemostatically normal. These clinical and biochemical observations have motivated investigations focused on alternative mechanisms for activation of factor XI independent of contact phase protein.19-22 Additional studies have focused on the identification and characterization of platelet factor XI, which is postulated to be an alternative splicing product of the factor XI gene. Platelet factor XI is present in platelet membranes and might substitute for plasma factor XI in hemostasis and account for the absence of bleeding complications in some patients with severe plasma factor XI deficiency.14,16-18,23-26 Studies addressing these two important and related problems are presented and discussed in this chapter.

Characterization of Recombinant Human Coagulation Factor XFriuli

1996 ◽  
Vol 75 (02) ◽  
pp. 313-317 ◽  
Author(s):  
D J Kim ◽  
A Girolami ◽  
H L James
Keyword(s):  
Catalytic Domain ◽  
Coagulation Factor ◽  
Molecular Size ◽  
Binding Pocket ◽  
Site Directed Mutagenesis ◽  
Bleeding Tendency ◽  
Factor X ◽  
Amino Terminal ◽  
Normal Plasma ◽  
Plasma Factor

SummaryNaturally occurring plasma factor XFriuli (pFXFr) is marginally activated by both the extrinsic and intrinsic coagulation pathways and has impaired catalytic potential. These studies were initiated to obtain confirmation that this molecule is multi-functionally defective due to the substitution of Ser for Pro at position 343 in the catalytic domain. By the Nelson-Long site-directed mutagenesis procedure a construct of cDNA in pRc/CMV was derived for recombinant factor XFriuli (rFXFr) produced in human embryonic (293) kidney cells. The rFXFr was purified and shown to have a molecular size identical to that of normal plasma factor X (pFX) by gel electrophoretic, and amino-terminal sequencing revealed normal processing cleavages. Using recombinant normal plasma factor X (rFXN) as a reference, the post-translational y-carboxy-glutamic acid (Gla) and (β-hydroxy aspartic acid (β-OH-Asp) content of rFXFr was over 85% and close to 100%, respectively, of expected levels. The specific activities of rFXFr in activation and catalytic assays were the same as those of pFXFr. Molecular modeling suggested the involvement of a new H-bond between the side-chains of Ser-343 and Thr-318 as they occur in anti-parallel (3-pleated sheets near the substrate-binding pocket of pFXFr. These results support the conclusion that the observed mutation in pFXFr is responsible for its dysfunctional activation and catalytic potentials, and that it accounts for the moderate bleeding tendency in the homozygous individuals who possess this variant procoagulant.

In Vitro Carboxylation of a Blood Coagulation Factor IX Precursor Produced by Recombinant-DNA Technology

1989 ◽  
Vol 61 (02) ◽  
pp. 238-242 ◽  
Author(s):  
Berry A M Soute ◽  
Alain Balland ◽  
Thérèse Faure ◽  
Henri de la Salle ◽  
Cees Vermeer
Keyword(s):  
Blood Coagulation ◽  
Recombinant Dna ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Recombinant Dna Technology ◽  
Coagulation Factor Ix ◽  
Recombinant Factor Ix

SummaryBlood coagulation factor IX (Christmas factor) is a plasma protein which is required for normal haemostasis. A functional deficiency of factor IX results in haemophilia B, a bleeding disorder which is generally treated by infusions of factor IX concentrates prepared from pooled human plasma. The use of human blood products is connected with the risk of transmitting viral agents responsible for diseases such as hepatitis B and AIDS. Recombinant DNA techniques may provide the means to produce the required proteins without exposing the patients to these risks and at lower costs. One of the problems which has to be overcome before recombinant factor IX can be used for therapeutical purposes is related to the vitamin K-dependent carboxylation of its 12 NH2-terminal glutamate residues. In cell cultures this carboxylation, which is required to render the protein its procoagulant activity, is far from complete, especially at high expression levels. In this paper we describe the in vitro carboxylation of non and/or partly carboxylated recombinant factor IX produced by transformed Chinese hamster ovary cells. The identity of the newly formed Gla residues was verified and it could be demonstrated that all carboxyl groups had been incorporated into the recombinant factor IX.

Coagulation Studies in a Case of Hageman Trait

1961 ◽  
Vol 05 (02) ◽  
pp. 187-200 ◽  
Author(s):  
E. A Loeliger ◽  
A Hensen
Keyword(s):  
High Activity ◽  
Blood Coagulation ◽  
Fibrinolytic Activity ◽  
Coagulation Factors ◽  
Normal Rate ◽  
Hageman Factor ◽  
Haemorrhagic Diathesis ◽  
Anticoagulant Property

SummaryAfter a brief review of the data concerning the cases of Hageman trait hitherto reported in the literature, a patient with severe Hageman factor (HF) “deficiency” (HF-activity below 0.05% of normal) is described. The patient has no haemorrhagic diathesis.In vitro, intrinsic coagulability and fibrinolytic activity are grossly disturbed. On the basis of a diminished fibrinolytic activity in vivo, the rather high activity of several coagulation factors in patient’s plasma could be explained.Thromboplastin formation, once initiated, is normal as to rate; the amount of thromboplastin formed is possibly slightly diminished. Prothrombin consumption is normal. These findings are in agreement with a normal rate ot clot formation, as measured by means of thrombelastography.Normal HF seems to be an initiator of blood coagulation only and not an activator or a substrate involved in thromboplastin formation.The weak anticoagulant property of Hageman trait plasma, described by several authors, is not necessarily due to an inhibitor; it can be explained by the assumption that, in Hageman trait, HF shows normal glass adsorbability and only a very deficient glass activation.

scholarly journals A Study of Lymphocyte Transformation as a Mechanism for Spontaneous Factor VIII Inhibitor Formation

1977 ◽  
Author(s):  
J. Katz ◽  
R. Lea ◽  
E.D. Gomperts
Keyword(s):  
Factor Viii ◽  
Mononuclear Cells ◽  
Lymphocyte Transformation ◽  
Factor Viii Inhibitor ◽  
Bleeding Tendency ◽  
Normal Plasma ◽  
Plasma Factor ◽  
Lymphocyte Cultures ◽  
Viii Inhibitor

Two elderly patients with a bleeding tendency due to spontaneous Factor VIII inhibition were investigated. An in vitro study was designed to investigate lymphocyte transformation and the production of Factor VIII inhibitor. Blood samples from patients were separated on a ficoll-hypaque gradient and the mononuclear cells were cultured with haemophiliac plasma. Factor VIII concentrate and normal plasma as sources of Factor VIII antigen. The results showed that the patients lymphocytes were stimulated by some samples of haemophiliac plasma, but not by the Factor VIII concentrates or normal plasma. However, normal control lymphocytes were similarly stimulated by these samples of haemophiliac plasma suggesting that immune complexes were present in the haemophiliac plasma and probably caused the stimulation. Furthermore, the patients lymphocytes were stimulated with phytohaemagglutinin candida and tuberculin and normal responses were obtained with AB serum. However, the sera of both patients inhibited candida and tuberculin stimulated lymphocyte cultures and the inhibition correlated with the presence of Factor VIII inhibitor. In this study a cellular immune mechanism for the production of spontaneous Factor VIII inhibitor could not be demonstrated, however a serum inhibitor of candida and tuberculin stimulated lymphocyte cultures was found.

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