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PubMed1987

New insights on vitamin K.

Vitamin K catalyzes the post-translational carboxylation of coagulation proteins C, S, and factors II, VII, XI, and X. Detection of the noncarboxylated forms allows an indirect and specific measure of the vitamin K deficiency found in early, classic, and late hemorrhagic disease of the newborn (HDN), malabsorption syndromes, and drug related (warfarin, anticonvulsants, and antibiotics) states. Idiopathic late HDN (CNS bleeding) occurs in exclusively breast-fed infants and is prevented by appropriate parenteral and oral vitamin K prophylaxis given at birth. All newborn infants and older infants with malabsorption syndromes should receive prophylactic vitamin K.

Child↗
PubMed2002

Investigation of coagulopathy in three cases of tiger snake (Notechis ater occidentalis) envenomation.

AIMS: To investigate the severe coagulopathy (fibrinogen < 1.0 g/l) that occurs in some cases of tiger snake envenomation. Specifically, to determine the concentration of clotting factors on presentation and during resolution of the coagulopathy. METHODS: Clotting factors II, V, VII, VIII, IX, XI were assayed on all coagulation samples received from three successive cases of severe tiger snake envenomations. Assays were performed at dilutions of 1:5 and 1:10 using an MLA 1600c automated coagulation analyser and Dade Behring factor-deficient plasmas, controls and standards. D-dimers were assayed using Agen Dimertest latex kit, fibrinogen was determined using the Clauss method and platelet counts were performed using Abbott Cell-Dyn 4000 analysers. RESULTS: The activity of the coagulation factors of the intrinsic pathway was reduced (factor VIII < 44% in all cases, factor IX < 33%, factor XI < 52% in Cases 1 and 2) but the results for the two dilutions were not parallel. In one case, factor VIII and factor IX activity increased 2-fold prior to the administration of blood products. Treatment with blood products corrected the coagulation indices in two out of the three cases but factor V remained low in one case (25%). CONCLUSIONS: The non-parallel results and the apparent increase in factor levels prior to treatment may result from the transient presence of an inhibitor to factors VIII, IX and XI in cases of tiger snake envenomation. Insight into the effects of snake venom on individual coagulation factors could be beneficial when considering new treatments for the coagulopathy induced by snake envenomation.

Adult↗
PubMed1993

Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation.

Factor XI (FXI) may be activated in a purified system by thrombin and by autoactivation in the presence of negatively charged substances such as dextran sulfate or sulfatides. The current studies were performed to determine if these processes occur during the coagulation of plasma. FXII--deficient plasma was supplemented with 125I-FXI and clot formation was induced with tissue factor and/or sulfatides. Cleavage of FXI was studied by standard polyacrylamide gel electrophoresis and autoradiography. Activated FXI (FXIa) was detected after 20 minutes of incubation with sulfatides alone and this process was markedly accelerated by the addition of tissue factor (TF). The enhancing effect of TF was blocked by hirudin, which indicated thrombin involvement in FXI activation. The contribution of FXIa to FIX activation in this system was studied using a 3H-FIX activation peptide release assay. Sulfatides increased FIX activation about twofold in plasma induced to clot with TF but had no effect if the plasma was immunodepleted of FXI. FIX activation was also increased in plasma induced to clot with FXa if sulfatides were present. The enhanced generation of FIXa was dependent on FXI and was blocked by hirudin. Some activation was seen in the reactions with sulfatides and hirudin and is likely solely caused by FXI autoactivation. The data indicate that during the coagulation of plasma in the presence of sulfatides, FXI is activated by a mechanism that is thrombin dependent and does not require FXII.

Blood Coagulation↗
PubMed1995

The current status of coagulation.

In 1964, the events of haemostasis were organized into the intrinsic and extrinsic pathways by the cascade/waterfall hypothesis, with primary physiological importance being given to the intrinsic pathway. Recent experimental evidence, as well as information about the clinical course of patients with various coagulation factor deficiencies, indicates a more prominent role for tissue factor. Rediscovery of the plasma protease inhibitor, tissue factor pathway inhibitor, and new information about the activation of factor XI have supported a revised theory of coagulation.

Amino Acid Sequence↗
PubMed1994

[A new cause of familial thrombophilia: resistance to the effect of activated protein C].

An examination of the cascade of events leading to coagulation emphasizes the importance of protein inhibitors. Deficiencies in these proteins have been implicated as playing a possible causal role in familial thrombo-embolic diseases. Recently the discovery of a probable deficiency in protein C cofactor, different from protein S, stimulated much research in this area. Protein C is a 461 amino acid vitamin K-dependent protein with a molar mass of 62,000 Daltons. After transduction the precursor protein is modified into an active form. Circulating protein C is then activated by proteolysis on the endothelial surface under the control of thrombomodulin-bound thrombin. Thus thrombin affects both procoagulation by activating factors V and VIII (and XI) and anticoagulation after being bound to thrombomodulin. Inactivation of factors V and VIII requires calcium, phospholipids and a C-protein cofactor, protein S. On the basis of clinical observations, it was hypothesized then confirmed that deficiency in a non-identified cofactor of protein C could explain resistance to the anticoagulating action of activated protein C. Purification of the plasma fraction carrying the cofactor activity led to the isolation of a protein which has all the biochemical properties of factor V. In addition, adding factor V to affected plasma has been shown to correct for resistance to activated protein C. But paradoxically, patients with resistance to the action of activated protein C have a normal level of factor V. The mutation responsible for activated protein C resistance was found to be a Gln for Arg mutation at position 506 of factor V. The implication of this mutation has been very recently confirmed and led rapidly to the development of molecular biology methods allowing its identification. At present, this new cause of familial hypercoagulable states can thus be identified with polymerase chain reaction and denaturing gradient gel electrophoresis. These advances have increased the number of identifiable hypercoagulable states, yet further work is needed since currently less than 10% of these diseases can be explained by deficiencies in one of the inhibitor proteins, antithrombin III, protein C or protein S.

Factor V↗
PubMed2002

Co-segregation of thrombophilic disorders in factor V Leiden carriers; the contributions of factor VIII, factor XI, thrombin activatable fibrinolysis inhibitor and lipoprotein(a) to the absolute risk of venous thromboembolism.

BACKGROUND AND OBJECTIVES: The clinical expression of factor V Leiden varies widely within and between families and only a minority of carriers will ever develop venous thromboembolism. Co-segregation of thrombophilic disorders is a possible explanation. Our aim was to assess the contributions of high levels of factor VIII:C, factor XI:C, thrombin activatable fibrinolysis inhibitor (TAFI) and lipoprotein (a) (Lp(a)) to the risk of venous thromboembolism in factor V Leiden carriers. DESIGN AND METHODS: Levels of the four proteins were measured, in addition to tests of deficiencies for antithrombin, protein C and protein S, and the prothrombin G20210A mutation, in 153 factor V Leiden carriers, derived from a family cohort study. The (adjusted) relative risk and absolute risk of venous thromboembolism for high levels of each protein were calculated. RESULTS: Of carriers, 60% had one or more concomitant thrombophilic disorders. Crude odds ratios (95% CI) of venous thromboembolism for high protein levels were: 3.2 (1.1-9.3) (factor VIII:C); 1.7 (0.6-4.9) (factor XI:C); 3.0 (1.1-8.2) (TAFI); and 1.9 (0.7-5.7) (Lp(a)). Adjusted for age, sex, other concomitant thrombophilic disorders and exogenous risk factors, the odds ratio for venous thromboembolism were 2.7 (0.8-8.7) for high factor VIII:C levels and 1.8 (0.6-5.3) for high TAFI levels. Annual incidences in subgroups of carriers were 0.35% (0.09-0.89), 0.44% (0.05-1.57) and 0.94% (0.35-2.05) for concomitance of high levels of factor VIII:C, TAFI and both, respectively, as compared to 0.09% (0.00-0.48) in single factor V Leiden carriers and 1.11% (0.30-2.82) for other concomitant disorders. INTERPRETATION AND CONCLUSIONS: High levels of factor VIII:C and TAFI, in contrast with factor XI:C and Lp(a), are mild risk factors for venous thromboembolism, and substantially contribute to the risk of venous thromboembolism in factor V Leiden carriers. Our data support the hypothesis that the clinical expression of factor V Leiden depends on co-segregation of thrombophilic disorders.

Adult↗
PubMed1998

The second exon-encoded factor XII region is involved in the interaction of factor XII with factor XI and does not contribute to the binding site for negatively charged surfaces.

Contact system activation, in vitro, is triggered by activation of factor XII (FXII) on binding to an activator, such as negatively charged surfaces. A putative surface-binding site of FXII has been located within the amino acid residues 1-28 by identifying the epitope recognized by a monoclonal antibody (MoAb), B7C9, which inhibits kaolin-induced clotting activity. To further elucidate the role of the amino terminal binding site in the regulation of FXII activation, we have characterized a FXII recombinant protein (rFXII-triangle up19) deleted of the amino acid residues 3-19, which are encoded by the second exon of FXII gene. A plasmid encoding for rFXII-triangle up19 was constructed and expressed in HepG2 cells by using vaccinia virus. Purified rFXII-triangle up19 migrated as a single band of Mr 77,000 on sodium dodecyl sulfate (SDS)-polyacrylamide gel, did not bind to MoAb B7C9 immobilized on Protein A-Sepharose, thus confirming that it lacked the epitope for this MoAb, and had no amidolytic activity towards the chromogenic substrate S-2302 in the absence of activator. rFXII-triangle up19 specific clotting activity was lower (44%) than that of native FXII. The activation rate of rFXII-triangle up19 by kallikrein in the absence of dextran sulfate was about four times higher than that of full-length FXII and was increased in the presence of dextran sulfate. However, rFXII-triangle up19 underwent autoactivation in the presence of dextran sulfate. Labeled rFXII-triangle up19 bound to kaolin, which binding was equally well inhibited by either, rFXII-triangle up19 or full-length FXII (IC50 = 7.2 +/- 2.2 nmol/L for both proteins). Accordingly, a synthetic peptide corresponding to FXII amino acid residues 3-19 did not inhibit the binding of labeled full-length FXII to kaolin. rFXII-triangle up19 generated a similar amount of FXIIa- and kallikrein-C1-inhibitor complexes in FXII-deficient plasma in the presence of kaolin, as did full-length FXII; but generated less factor XIa-C1-inhibitor complexes (50%) than full-length FXII. This impaired factor XI activation by rFXII-triangle up19a was also observed in a purified system and was independent of the presence of high molecular weight kininogen. Furthermore, the synthetic peptide 3-19, preincubated with factor XI, inhibited up to 30% activation of factor XI both in the purified system as well as in plasma. These results together indicate that amino acid residues 3-19 of FXII are involved in the activation of factor XI and do not contribute to the binding of FXII to negatively charged surfaces.

Blood Coagulation↗